Intro To Clinical Sciences Flashcards
What is the suffix for neoplasms?
-oma
What is the definition of a neoplasm?
Lesion resulting from the autonomous abnormal growth of cells which persists after the initiating stimulus has been removed
Are neoplastic cells usually monoclonal or not?
Yes they are but once the neoplasm has started growing the cells won’t necessarily stay monoclonal.
What is the stroma of a neoplasm?
The support- connective tissue framework to provide mechanical support and nutrition
What cell and tissue types would you expect to find within a neoplasm’s stroma?
Fibroblasts, collagen, myofibroblasts and many blood vessels
What is angiogenesis?
Growth of new blood vessels
What factor determines the ability of a neoplasm to grow?
Presence of blood vessels
Can only grow to around 2mm whilst using diffusion only, past this size they need vascularisation
What are 6 features of benign neoplasm?
- Localised and non-invasive
- Slow growth rate in comparison to malignant so low mitotic activity
- Necrosis and ulceration are rare as they don’t outgrow their blood supply
- Close resemblance to normal tissue
- Circumscribed or encapsulated
- Often exophytic= up and out
What are 6 features of malignant neoplasms?
- Invasive- mastastases
- Rapid growth rate so high mitotic activity
- Variable resemblance to normal tissue
- Poorly defined/irregular border
- Hyperchromatic (dark) nuclei
- Necrosis and ulceration common as outgrows blood supply
What is a papilloma?
Benign
Non-glandular
Non-secretory
Epithelium
Neoplasm
What is being described here:
Benign
Non-glandular
Non-secretory
Neoplasm
Papilloma
What is an adenoma?
Benign
Glandular or secretory
Epithelium
Neoplasm
What is being described here:
Benign
Glandular or secretory
Epithelium
Neoplasm
Adenoma
What is a carcinoma?
Malignant tumour of epithelial cells
What is being described here:
Malignant tumour of epithelial cells
Carcinoma
Name the benign connective tissue neoplasms for the following:
Adipocytes
Cartilage
Bone
Vascular
Striated muscle
Smooth muscle
Nerves
Lipoma
Chondroma
Osteoma
Angioma
Rhabdomyoma
Leiomyoma
Neuroma
What is the suffix for a malignant connective tissue neoplasm?
-sarcoma
What are the exceptions where -oma is malignant?
Melanoma
Mesothelioma
Lymphoma
What is the definition of Carcinogenesis?
Transformation of normal cells to (malignant) neoplastic cells through permanent genetic alterations or mutations- which are always multistep
What is the definition of oncogenesis?
Transformation to malignant or benign neoplastic cells
What is the definition of carcinogenic?
Cancer causing
What is the definition of oncogenic?
Tumour causing
What are 5 classes of carcinogens?
Chemical
Viral
Ionising & non-ionising radiation
Hormones, paracytes and mycotoxins
Miscellaneous
What are 4 examples of viral carcinogens?
HPV
Herpes virus 8
Hep B
Merkle cell polyomavirus
What are 8 host factors for cancer risk?
Ethnicity
Age
Sex
Sexual behaviours
Diet/exercise
Premalignant conditions (eg polyps)
Inherited predisposition
Trans-placental carcinogenesis
What is a latent interval?
The time between exposure to a carcinogen and the time the cancer “begins”
What are the main stages (as in titles- very brief) involved in the formation of an atherosclerotic plaque?
Initial lesion
Fatty streak
Plaque progression
If it is unstable the plaque may then rupture
Which cells produce collagen in fibrous scarring?
Fibroblasts
Give examples of where granulomatous inflammation occurs (where collection of macrophages surrounds lymphocytes)
May be due to a myobacterial infection such as TB or leprosy
Seen in chron’s and sarcoidosis
Which 4 main cells are seen in inflammation?
Neutrophil polymorphs
Macrophages
Lymphocytes
Fibroblasts
Which cell is being described:
White blood cell made in bone marrow
Short lifespan of 2-3 days
Polyobed nucleus
Eat debris and bacteria
Contain lysosomes
Neutrophil polymorph
Which cell is being described:
White blood cell
Long lifespan (months-years)
Phagocytose debris and bacteria
Antigen presenting cells- secondary immune response
Macrophages
Which cell is being described:
Long-lived, for years
Control inflammation and antibodies
Immunological memory cell
Lymphocyte
What is the sequence of acute inflammation?
- Injury/infection
- neutrophils arrive, phagocytose and release enzymes
- macrophages arrive and phagocytose
- resolution with clearance/ progress to chronic
What are 3 examples of acute inflammation and what is another name for it?
= neutrophil-mediated
Acute appendicitis
Frostbite
Streotococcal sore throat
What is the sequence of chronic inflammation and what can it also be called?
= macrophage/lymphocyte mediated
Either progresses from acute of starts as ‘chronic’
Starts with macrophages and lymphocytes then usually fibroblasts
If there is no tissue damage then it can be resolved but often ends up with repair and formation of scar tissue
How would you treat inflammation if you wanted to?
Ice- stops capillaries from being flooded with blood and fluid escaping
Antihistamine- histamine is a chemical mediator of acute inflammation
Ibuprofen- inhibits prostaglandin sythetase
Steroids- upregulate inhibitors of inflammation, downregulates mediators
Which of the following tumours never metastasises?
• Malignant melanoma
• Small cell carcinoma of the lung
• Basal cell carcinoma of the skin
• Breast cancer
Basal cell carcinoma
Which of the following tumours does not commonly metastasise to bone?
• Breast cancer
• Lung cancer
• Prostate cancer
• Liposarcoma
Liposarcoma
Those that do are breast, lung, prostate, renal cell and thyroid
What is the name of malignant tumour of striated muscle?
Rhabdomyosarcoma
What term describes a cancer that has not invaded through the basement membrane?
Carcinoma in situ
What is the name of a benign tumour of glandular epithelium?
Adenoma
Which of these tumours does not have a screening programme in the UK?
• Breast
• Colorectal
• Cervical
• Lung
Lung
What is the name of benign tumour of fat cells?
Lipoma
What is the name of a malignant tumour of glandular epithelium?
adenocarcinoma
Which of the following is not a feature of malignant tumours?
• vascular invasion
• Metastasis
• Increased cell division
• Growth related to overall body growth
Growth related to overall body growth
A transitional cell carcinoma of the bladder is a malignant tumour?
• True
• False
True
A leiomyoma is a benign tumour of smooth muscle?
• True
• False
True
Radon gas is a cause of lung cancer?
• True
• False
True
Which tumour has the shortest median survival?
• Basal cell carcinoma
• Malignant melanoma
• Breast cancer
• Anaplastic carcinoma of the thyroid
Anaplastic carcinoma of the thyroid
Ovarian cancer commonly spreads in the peritoneum?
• True
• False
True
What are reasons for an autopsy?
Cause of death not known
Presumed iatrogenic
Anaesthetic deaths
Abortion
Complications of therapy
Presumed unnatural
Suicide (by legal diagnosis)
Unlawful killing
Neglect
Custody deaths
War
Industrial deaths
What is apoptosis?
Programmed cell death in normal cell turnover
How does apoptosis occur?
P53 protein detects DNA damage and triggers apoptosis if appt.
Enzymes are released which auto digest the cell (many of these enzymes = caspases)
In which diseases is apoptosis relevant?
Cancer- cells often don’t apoptose, sometimes due to mutation in p53 gene so can no longer detect damage
HIV- HIV can induce apoptosis (in CD4 helper cells)
What is necrosis?
Wholesale destruction of large numbers of cells by some external factor
What are 4 clinical examples of necrosis?
- Infarction due to loss of blood supply
- Frostbite
- Toxic venom from reptiles and insects
- Pacreatitis
Define hypertrophy:
Increase in size of an organ due to increase in the size of its constituent cells
Define hyperplasia:
Increase in size of an organ due to increase in the number of its constituent cells
Where do hypertrophy and hyperplasia occur:
Hypertrophy= in organs where cells cannot divide
Hyperplasia= in organs where cells can divide
Mixed hypertrophy/hyperplasia occurs in organs where cells can divide
What is an example of mixed hypertrophy/hyperplasia?
Smooth muscle cells of the uterus during pregnancy
Define atrophy:
Decrease in size of an organ due to decrease in size and/or number of its constituent cells
Define metaplasia:
Change in cell differentiation from one fully-differentiated type to another fully-differentiated type (usually caused by consistent change in environment)
What is one example of metaplasia?
Barrett’s oesophagus
Oesophageal squamous epithelium to glandular epithelium in continued acid reflux from the stomach
Define dysplasia:
=abnormal growth
Morphological change that may be seen in cells in the progression on to development of cancer (neoplasia)
What is an example of dysplasia?
Bronchial epithelium in cigarette smokers- metaplasia from ciliated to squamous
What are the two types of bone metastases?
Sclerotic (increases BMD)
Lytic (reduced BMD)
What are 4 tumour which commonly metastasise to the liver?
Colon
Stomach
Pancreas
Carcinoid tumours of intestine
Why do many tumours metastasise to the lung?
Because the metastases become lodged in the small pulmonary vessels
The lungs act like a filter for tumours
Why is tumour angiogenesis important?
Because tumours cannot grow above ~2mm when they have no blood supply
If we can find a way to stop angiogenesis- we can find a way to stop tumours growing?
What are 3 factors that allow extravasation of tumour cells?
Adhesion receptors
Collagenases
Cell motility
What is the role of matrix metalloprotinases in cancer?
These are produced to help the cancer metabolise collagen and the basement membrane
• Which of these is an example of acute inflammation:
◦ Glandular fever
◦ Leprosy
◦ Appendicitis
◦ Tuberculosis
Appendicities
In which of the following does granulomatous inflammation occur: =helpful clinical presentation of collection of macrophages surrounded by lymphocytes
◦ Chron’s
◦ Acute appendicitis
◦ Infectious mononucleosis
◦ Lobar pneumonia
Chron’s
• Which of the following is a chronic inflammatory process from its start:
◦ Appendicitis
◦ Cholecystisis
◦ Infection mononuleosis
◦ Lobar pneumonia
Infection mononucleosis
= mono = glandular fever
• Which of the following is an example of hyperplasia:
◦ Bodybuilder’s biceps
◦ Enlarged left ventricle
◦ Benign prostate enlargement
◦ Wasting of quads after immobilisation
Benign prostate enlargement
• Which is not an example of apoptosis:
◦ Loss of cells from tips of duodenal villi
◦ Loss of cells during embryogenesis
◦ Renal infarction
◦ Graft versus host disease
Renal infarction
= necrosis
• Which is an example of atrophy:
◦ Biceps of bodybuilder
◦ Uterus in pregnancy
◦ Brain in dementia
◦ Prostate in older age
Brain in dementia
What two factors mean that blood clots are rare?
Laminar flow= cells travels in the centre of vessels not touching the sides
Endothelial cells lining vessels are not ‘sticky’ until they are damaged
Define thrombosis:
The formation of a solid mass from blood constituents in an intact vessel in a living person
What are the 3 ‘causes’ of thrombosis?
Change in vessel wall
Change in blood constituents
Change in blood flow
Define embolus:
Mass of material in the vascular system able to become lodged within a vessel and block it
What can an embolus be?
Most commonly a thrombus
Sometimes air, cholesterol crystals, tumours and fat
Define ischaemia:
Reduction in blood flow to a tissue without any other complications
Define infarction:
Reduction in blood flow to a tissue that is so reduced it can no loner support the mere maintenance of cells in the tissue so they die
Define congenital:
Present at birth- can be inherited or environmental
What 2 cell types don’t regenerate?
Myocardial cells
Neurones
What is the difference between resolution and repair?
Resolution= initiating factor removed and tissue left undamaged or able to regenerate
Repair= initiating factor is still present and tissue left damaged or unable to regenerate
What is healing by primary and secondary intention?
Primary intention- when wound edges are clean, surgically incised, without much loss of cell/tissue and wounds have opposed edges
Secondary intention- wound edges are not clean, margins are irregular, and not surgically incised
Are the following examples of repair or resolution?
Heart after myocardial infarction
Brain after cerebral infarction
Spinal cord after trauma
Repair
When a bone is fractured and kept stable what is happening- resolution or repair?
Resolution
When a bone is fractured and NOT kept stable what is happening- resolution or repair?
Repair
What is atherosclerosis?
Accumulation of fibrolipid plaques in systemic arteries
What are the 4 main risk factors for atherosclerosis?
Hypertension
Hyperlipidaemia
Cigarette smoking
Poorly-controlled diabetes
What is the current theory behind atherosclerosis?
Endothelial cells are delicate- can be damaged by smoking, lipids, oxidative agents etc.
Damage leads to endothelial ulceration, microthrombi, eventual development of established atherosclerotic plaques.
Give the process of atherosclerotic plaque formation:
- Damage to endothelium- becomes permeable to LDLs
- LDLs deposit in tunica intima and become oxidised- now they can’t leave
- Oxidised LDLs activate endothelial expressions for WBCs so monocytes are taken into intima
- Monocytes -> macrophages + LDL = FOAM
- FOAM release lipids when they die= plaque
What are the main ‘types’ of drugs?
Enzyme
Ligand
Transporter
Channel
What are the types of ligands?
Exogenous (drugs)
Endogenous (hormones, neurotransmitter)
What are the 4 types of receptors?
Ligand-gated ion channels (nicotine, ACh)
G protein coupled receptors, GCPR (beta-andrenoceptors)
Kinase-linked receptors (growth factors)
Cytosolic/nuclear receptors (steroid)
What controls the activity of g-protein coupled receptors?
Regulated by factors that control their ability to bind to and hydrolyze GTP to GDP
For the following receptors, what are their G proteins, couples and 2nd messengers?
M3R
B2-AR
M3R: Gq protein, PLC couple, IP3/DAG 2nd mes.
B2-AR: Gs protein, AC couple, cyclic AMP 2nd mes.
How do kinase-linked receptors work?
Kinases are enzymes which catalyse the transfer of phosphate groups between proteins- substrate gains phophate from ATP
Receptors are activated when the binding of an extracellular ligand causes enzymatic activity on the intracellular side
How to nuclear receptors work?
By modifying gene transcription
What is a drug’s intrinsic activity?
The ability of a drug-receptor complex to produce a maximum functional response
What is a drug’s potency?
The response given by a drug at a given dose
What is the efficacy of a drug?
How ‘much’ it works- ie. Does it give a 100% response at a given dose
What is competitive vs non-competitive antagonism?
When two drugs have opposing effects.
In competitive they bind to the same site
In non-competitive the antagonist binds to an allosteric site.
What are the receptor-related and tissue-related factors that govern drug action?
Receptor-related: affinity and efficacy
Tissue related: receptor number and signal amplification
What is drug affinity?
How well the ligand binds to the receptor
What is efficacy of ligands?
How well the ligand activated the receptor
What is the affinity and efficacy of agonists and antagonists?
Agonists have both affinity and efficacy- some more than others.
Antagonists have affinity and ZERO efficacy
What is bromacetyl alprenolol menthan (BAAM)?
An irreversible antagonist- once bound to the receptor, it will not com off
What is the receptor reserve?
When a response is seen when not all receptors have been stimulated so there are spare receptors even though a response is seen
What are two pathological examples of where there is an imbalance of chemicals and receptors?
In allergies where there is too much histamine
In Parkinson’s where there is too little dopamine
What are agonistic and antagonistic ligands?
Agonists activate a receptor when bound
Antagonists reduce the effect of a receptor when bound
What is inverse agonism?
When a drug that binds to the same receptor as an agonist induces a response opposite to that of the agonist.
What is drug tolerance?
When there is a reduction in the effect of the agonist over time often when there are continuously high concentrations
What is drug desensitisation?
The rapid desensitisation to a drug which is uncoupled, internalised and degraded
What are isoprenaline and salbutmaol?
Isoprenaline is a non-selective B-adrenoceptor agonist.
Salbutamol is selective- will only activate the receptors in the lungs where as Iso is non-specific
Define physicochemical:
How two drugs interact independent of the body- so the way they interact has nothing to do with any body systems or environments.
Define pharmacodynamics:
The effect a drug has on the body
(Not always the primary effect)
Define pharmacokinetics:
What the body does to the drug.
How a drug is absorbed, distributed, metabolised and excreted.
What are the 4 types of pharmacodynamic drug interactions?
Summation/additive
Synergism
Antagonism/blockade
Potentiation
What is summative/additive pharmacodynamic drug interaction?
When two drugs work together to do the same thing and have an effect equal to the sum of their individual effects.
What is synergistic pharmacodynamic drug interaction?
When two drugs work together to produce a response greater than the sum of both individual responses
What is antagonistic/blockage pharmacodynamic drug interaction?
When one drug antagonises/blocks the effect of another so 1+1=0
What is Potentiation pharmacodynamics in drug interactions?
When one drug makes the effect of another more potent without changing itself.
What is pharmacokinetics ADME?
A- absorption
D- distribution
M- metabolism
E- excretion
Most drugs are hepatically metabolised and renally excreted
What is bioavailability?
How available a drug is over time (use area under graph of blood concentration x time)
Fraction of an administered drug that reaches the systemic circulation
Why would acidity affect drug absorption?
Because all drugs exist in an equilibrium of their ionised and unionised states- where the unionised drugs can move into cells though the bilayer.
PH affects the equilibrium and therefore how much drug can pas into the cells
What is enzyme induction and inhibition in pharmokinetics?
How some drugs up or down regulate the enzymatic change of a drug into its active form therefore up or down regulating the active drug
Give 2 examples where you should remember drug interactions?
Warfarin (in context of protein binding and enzyme inhibition/induction)
And any that may induce acute kidney injury (ace inhibitors, NSAIDs, furosemide and gentimicin)
What are the two categories of cholinergic receptors?
Nicotinic and muscuarinic
What do statins do chemically?
Block the rate limiting step in the cholesterol pathway- reduces levels of “bad cholesterol”
What are 4 ways in which enzyme inhibitors can be used to treat Parkinson’s?
Carbidopa inhibitor for DDC (L-dopa -> dopamine)
Tolcapone inhibitor for COMT (L-dopa -> 3-methyl DOPA) both in periphery and in CNS
Selegiline inhibitor for MAO-B (dopamine -> DOPAC)
What are the 3 main types of protein ports in cell membranes, and what are they?
Uniporters= use energy from ATP to pull molecules in
Symporters= use the movement in of molecules to pull in another molecule against a concentration gradient
Antiporters = one substance moves against its gradient using energy from a second substance moving with its gradient
How does furosemide target NKCC?
It inhibits trasport in NKCC (sodium potassium chlorine cotransported).
= a diuretic so inhibits
What would we see if epithelial (sodium ) channel failed?
Heart failure
What would we see if voltage-gated channel failed?
Nerve failure and arrhythmia
What would we see if metabolic (potassium) channel failed?
Diabetes
What would we see if receptor activated (chloride) channel failed?
Epilepsy
What does heterotrimeric mean?
Has two sets of three independent proteins- multiple genes code for different sub-units
What channels are blocked by high affinity diuretics?
ENaC= epithelial sodium channels
Where are voltage gated calcium channels found?
Often at excitable cells such as muscle and neurones
How are voltage-gated calcium channels opened?
They are normally found closed, but are activated at depolarised membrane potentials- Ca2+ enters the cell and the Ca-sensitive K channels are opened …
What channel does amlopdipine work on?
Voltage gated calcium channels- inhibits contraction of cardiac muscle
Causes vasodilation to lower blood pressure
What channels does lidocaine affect and what does it do?
Lidocaine= anaesthetic
It blocks transmission of action potential to voltage gated sodium channels
What are the 3 conformational states of voltage gated channels?
Closed
Open
Inactivated
What is one place where voltage gated K channels are important?
Regulation of insulin in the pancreas- increased glucose leads to block of these channels and opening of Ca2+ channels so insulin release is triggered
Where/ how do repaglinide, nateglinide and sulfonylyureal all act?
On voltage gated K channels- block them so insulin is secreted
So used to treat type 2 diabetes
Where/how does digoxin act?
On the Na/K ATPase- mainly in the myocardium
Used for atrial fibrillation and heart failure
Inhibition causes an increase in intracellular Na so there is decreased activity in Na-Ca exchanger and hence less Ca in intracellularly
Slows down action potential therefore slows down heart rate
What is the proton pump : K/H ATP-ases targeted for the treatment of?
This is the proton pump of the stomach and is responsible for the acidification of the stomach so inhibition of this inhibits acid secretion
What does omeprazole target?
Proton pumps in the stomach to lower stomach pH
What are 3 non-medical examples of irreversible enzyme inhibitors?
Nerve gases (sarin)
Insecticides
Pesticides
What are 5 drugs that are irreversible enzyme inhibitors?
Omeprazole (proton pump inhibitor)
Ramiprill (ACE inhibitor)
Aspirin (COX inhibitor)
Paracetamol (COX inhibitor)
Simvastatin (statin)
What does xenobiotic mean?
Compound foreign to an organism’s normal biochemistry eg any drug or poison
What are cytochrome P450s and what do they do?
Primarily membrane associated monoocidase proteins in the mitochondria/ER
They are major enzymes of drug metabolism
Most drugs undergo deactivation by CYPs, some are activated to their active compounds
What are the naturally occurring opioids?
Morphine
Codeine
What are the simply chemically modified opioids?
Diamorphine
Oxycodone
Dihydrocodeine
What are the 4 synthetic opioids?
Pethidine
Fentanyl
Alfentanil
Remifentail
What are opioid’s synthetic partial agonist and antagonist?
Synthetic partial agonist: buprenorphine
Antagonists: naloxone
How much oral morphine is metabolised by first pass metabolism in the liver?
50%
With morphine, what would the equivalent intramuscular or IV dose be for 10mg of oral morphine?
5mg
50% of oral is metabolised by liver
What are 4 routes of administration for morphine?
Paranteral (not oral)- IM, IV, subcutaneous
IV patient controlled analgesia
Epidural/CSF
Trans-dermal patches for lipid soluble drugs eg fentanyl
Which is more potent and faster acting, morphine or diamorphine?
Diamorphine
What is heroin?
Diamorphine
How do opioids work?
Inhibit the release of pain transmitters at the spinal cord and midbrain giving euphoria- changes the emotional perception of pain
Act on g-protein coupled receptors via second messenger
Why are opioids addictive?
They act on the descending inhibition of pain- part of fight or flight
These were never designed for sustained activation (which opioids provide) and sustained activation leads to tolerance and addiction
What are the 4 opioid receptors?
Mu (MOP)
Delta (DOP)
Kappa (KOP)
Nociceptin (NOP)
Why do we use MOP agonists instead of KOP agonists?
MOP agonists cause depression instead of euphoria
What are the relative potencies of diamorphine, morphine and pethidine?
5
10
100
What is the difference between dependence and tolerance?
Tolerance is the down regulation of receptors that occurs with prolonged use of a drug- where you then need a higher dose to achieve the same effect
Dependence is the psychological effects- craving, euphoria etc
What are the timings of opioid withdrawal?
Starts within 24 hours and lasts around 72
What are 7 side effect of opioids?
Respiratory depression
Sedation
Nausea and vomiting
Constipation
Itching
Immune suppression
Endocrine effects
What do you do if someone is experiencing opioid induced respiratory depression?
ABC (+ 999)
Naloxone
IV- titration to effect- 1ml in 10ml saline- don’t give it all at once
What is opioid induced respiratory depression?
Combination of opioid-induced central respiratory depression (reduced respiratory drive), decreased level of consciousness and upper airway obstruction due to decrease in supraglottic airway tone.
For what reason were opioids heavily marketed n the US in the 90s?
For treatment of chronic non-cancer pain
Why do we need to be aware of CYP2D6 in individuals taking codeine?
Codeine is metabolised by CYP2D6
It’s activity is decreased n=in 10-15% of Caucasian population and absent in a further 10%- in these people codeine will have a reduced or absent effect
CYP2D6 is overactive in 5% of this population so these may be at risk of respiratory depression with codeiene
How is morphine metabolised?
To morphine 6 glucuronide which is more potent than morphine and is renally excreted
What is tramadol, how is it metabolised?
A weak opioid agonist- slightly stronger than codeine
Is metabolised by CYP2D6 to o-desmethyl tramadol to be active- therefore won’t be effective in about 10% of people
Why do we need to think about how tramadol interacts with certain drugs?
It has effects as a serotonin and nor-epinephrine reuptake inhibitor
It interacts with SSRIs, tricyclic antidepressants and MAOIs
What are the features of type 1 hypersensitivity reactions?
= allergy
Antigen reacts with IgE bound to mast cell
Eg. Anaphylaxis
What are the features of type 2 hypersensitivity reactions?
IgG or IgM binds to antigen on cell surface
Antibody mediated immune response
Eg. Pernicious anaemia, rheumatic fever
What are the features of type 3 hypersensitivity reactions?
Free antigen and antibody combine (IgG, IgA) to form immune complex
Eg. Systemic lupus erythematosus
What are the features of type 4 hypersensitivity reactions?
=T-cell mediated
=Delayed type hypersensitivity
Cell dependant (Th1/cytotoxic T cells/macrophages)
Divided into 3 subgroups: damage caused activation of macrophages, activation of TH2 cells and directly by cytotoxic T cells
Eg. Tuberculosis
What are examples of hypersensitivity reactions for types 1-4?
1: allergy, asthma, anaphylaxis
2: some drug allergies eg penicillin
3: serum sickness, contact dermititis
4: chronic asthma, contact dermititis
What are the clinical presentations of allergy in skin, airways, GI and anaphylaxis?
Skin: swelling, itching and red
Airways: excessive mucus production, bronchoconstriction
GI: abdominal bloating, vomiting, diarrhoea
Anaphylaxis: airways, breathing, circulation etc.
What are allergies?
Abnormal responses to harmless foreign materials
What are the 7 allergic diseases?
Anaphylaxis
Allergic asthma
Allergic rhinitis (hay fever)
Atopic dermatitis
Oral allergy syndrome (food allergy)
Angiodema (not idiopathic one)
What are the 3 main mediators of allergy?
Cytokines
Chemokines
Lipids
What are the 3 main cells of allergy?
Mast cells
Eosinophils
Basophils
What is the average serum concentration of IgE?
0.3-100 micrograms/ml
What is the difference/similarities between eosinophils and basophils?
Eosinophils respond in parasitic infections. They have an antagonistic action to basophils and have IgE receptors
Basophils are involved in inflammatory reactions= the circulating form of MAST cells. They also have receptors for IgE and release histamine
How are mast cells developed and what are they characterised by?
Produced by a specific cell lineage in marrow
Characterised by a requirement for c-kit protein (systemic mastocytosis= caused by c-kit mutations)
What proteins binds to IgE?
FceRI = high affinity
FceRII= low affinity
CD23= low affinity
Which 6 cells express FceRII and CD23 and what is their function in this context?
B cells, T cells, monocytes, eosinophils, platelets and neutrophils
Their functions are to regulate IgE synthesis, trigger cytokines release by monocytes and to present antigens
What are the 3 main cells that express FceRI?
Eosinophils
Mast cells
Basophils
What is the immediate response from mast cells?
They have preformed compounds:
Histamine (arteriolar dilation, capillary leakage and cholinergic reflex bronchoconstriction)
Chemotactic factors (cytokines)
Proteases (tryptase, chymase)
Proteoglycans (chondroitin sulphate and heparin)
Most of these factors lead to eosinophil attraction and activation
What are the responses of Mast cells within minutes and within hours?
Within minutes they release lipid derived mediators:
Leukotrienes (endothelial contraction with vascular leakage), prostaglandin D2 (inducer of smooth muscle contraction), platelet activating factor (increased platelet aggregation).
Within hours they release cytokines IL-8, IL-5, IL-4, IL-14 and RANTES
What are direct activators of mast cells?
Cold/mechanical deformation (Asthma?)
Aspirin
Tartrazine
NO2
Latex
What are indirect activators of Mast cells?
Indirect because they act via IgE
Allergens such as latex, venom, foods, drugs, dander- for these prior sensitisation is required
Bacterial viral antigens
What are the roles of the following cells in allergy:
Lymphocytes
Dendritic cells
Neurons
Lymphocytes (th2)
Dendritic cells (for antigen presentation)
Neurons (cholinergic/andrenergic)
What are 4 features of asthma?
Complex inflammatory disease of the bronchi
Commonly triggered by allergens
Can involve eosinophil influx to the lungs
Often involves IgE
What is atopy?
A hereditary predisposition to the development of immediate hypersensitivity reactions against common environmental antigens
What are 3 features of chronic asthma?
Non-Th2 cell mechanism
CD8 T cells control eosinophil responses
Similar to type 4 hypersensitivuty
How can we use desensitisation in allergy treatment?
= immunotherapy
Increasing doses of antigen sub-lingually or sub-cutaenously
There are risks of moderate and life-threatening reactions
How can we use IgE prevention to treat allergies?
Can we supress Th2?
Can we deliver suppressive cytokines?
We can use anti-DC23 antibodies to decrease IgE levels
What is one example of anti-IgE therapy and what are the downsides to it?
Xolair (selectively binds to IgE)
= inhibits the binding of IgE to FceRI
It is very costly, slightly increases cancer incidence
What are 6 treatment strategies for allergy?
Avoid allergens
Desensitisation to allergens
Prevent IgE production
Prevent IgE interaction with receptor
Prevent mast cell activation
Inhibit mast cell products
What are the 4 main anti-cytokine antibodies?
IL-5 antibody= mepolizumab
IL-5 receptor antibody= reslizumab, benralizumab
Anti IL-4/IL-13 = depilumab
What are 5 ways in which we can reduce mast cell activation to treat allergies?
Mast cell stabilisers
Beta2 agonists (increase cAMP)
Glucocorticoids (inhibit gene transcription)
Calcium channel blockers
Signalling inhibitors
What are the ways in which we can inhibit mast cell products to treat allergy?
Histamine receptor agonists
Leukotriene antagonists
Tryptase inhibitors (prevent airway smooth muscle activation)
Protease-activated receptor 2 agonists (PAR-2 agonists)
What are the 3 main stages of drug development?
Drug discovery
Preclinical development
Clinical development
What are the medications derived from the foxglove plant?
Digitalis
What are the medications derived from poppies?
Morphine
What are the medications derived from deadly nightshade?
Atropine
What are the medications derived from periwinkle?
Vincristine
What are three approaches to neutralisation of tumour necrosis factor a?
Chimeric antibody (infliximab)
Fusion protein (etanercept)
Human antibody (adalimumab)
What are the features of infliximab? (Derivative, use etc)
It is a monoclonal antibody from mice against TNF alpha
Initially used for chron’s disease now for rheumatoid arthritis also
Given by IV infusion every 6-8 weeks
What is adalimumab (humira)
HUman Monoclonal antibody In Rheumatoid Arthritis
Define adverse drug reaction:
Unwanted or harmful reaction following administration of a drug or combination of drugs under normal conditions of use and is suspected to be related to the drug
What is the difference between adverse drug reaction and side effects?
Side effects can be beneficial but adverse drug reaction are ALWAYS negative
What are the 3 types of adverse drug reaction?
Toxic effects (when beyond the therapeutic range)
Collateral effects (when within the therapeutic range)
Hyper-susceptibility effects (when below the therapeutic range)
What are two reasons a toxic adverse drug effect may occur?
If dose is too high
If excretion is impaired
What are the ~7 patient risk factors for adverse drug reactions?
More common in women
More common at extreme ages (old and young)
Polypharmacy
Genetic predisposition
Hypersensitivity
Hepatic/renal impairment
Adherence problems
What are the drug risk factors for adverse drug reactions?
Low therapeutic index (easy to reach toxic range)
Steep dose-response curve
What are the 7 causes of adverse drug reactions?
Pharmaceutical variation
Receptor abnormality
Abnormal biological system that is unmasked by the drug
Abnormalities in drug metabolism
Immunilogical
Drug-drug interactions
Multifactorial
What are the 6 time dependent adverse drug reactions?
Rapid reactions (eg due to quick histamine release with rapid administration of vancomycin)
First dose reactions
Early reactions
Intermediate reactions
Late reaction (maybe when drug is stopped)
Delayed reactions (thalidomide in pregnancy)
Give the Rawlins Thompson classification:
Type A = Augmented pharmacological
Type B = Bizarre or idiosyncratic
Type C = Chronic
Type D = Delayed
Type E = End of treatment
Type F = Failure of therapy
Give the features of type A drug reactions:
= augmented
Predictable, dose dependent, common
Excludes drug abuse and overdose
Give the features of type B drug reactions:
= bizarre
Not predictable, not dose dependent
Eg. Anaphylaxis from penicillin
Less common but more often serious
Can be allergy or hypersensitivity
Give the features of type C drug reactions:
= chronic
Eg. Osteoporosis from long term steroids
Uncommon and related to cumulative dose
Give the features of type D drug reactions:
= delayed
Eg malignancies after immunosuppression
Usually dose related and uncommon
Give the features of type E drug reactions:
= end of treatment
May occur after abrupt drug withdrawal eg. Opiate withdrawal syndrome
Give the features of type F drug reactions:
= failure
Eg. Getting pregnant on the pill because taking other antibiotics
What is DoTS in the context of adverse drug reactions?
Dose relatedness
Timing
patient Susceptibility
What are 4 things to look out for if an adverse drug reaction is suspected?
Symptoms soon after new drug is started
Symptoms after dosage increase
Symptoms disappear when drug is stopped
Symptoms reappear when drug is restarted
What are the 7 most common drugs to have ADRs?
Antibiotics
Anti-neoplastics
Cardiovascular drugs
Hypoglycaemics
NSAIDs
CNS drugs
What is the yellow card scheme?
A scheme to report ADRs
These only need to be suspected
It is voluntary
What do you report on a yellow card?
All suspected reactions for herbal medicine
All suspected reactions for black triangle drugs (undergoing observation even though they’re on the market)
All serious suspected reactions for established drugs, vaccines and drug interactions
What is the black triangle?
Used to indicate medicine that are undergoing additional monitoring
What 4 pieces of information needed to be included on a yellow card?
Suspected drug(s)
Suspected reaction(s)
Patient details
Reporter details
What are examples of immediate and delayed drug hypersensitivity?
Immediate- urticarial (rash), anaphylaxis
Delayed- hepatitis, other rashes
Which type of hypersensitivity is anaphylaxis?
Type 1
What are the features of type 1 hypersensitivity- anaphylaxis?
Had a prior exposure
IgE antibodies formed after exposure
IgE becomes attaches to mast cells
Re-exposure causes mast cell degranulation and release of substances such as histamine
What is non immune anaphylaxis?
Due to direct mast cell degranulation
No prior exposure necessary
Clinically identical to immune anaphylaxis
What are the main features of anaphylaxis?
Immediate rapid onset after exposure to drug (80-90%)
Swelling of lipids, face, oedema
HYPOtension
Cardiac arrest
How do we manage anaphylaxis?
Basic life support
Stop drug if possible
Adrenaline (Intramuscular- epi-pen is 300mcg, hospital is 500mcg)
High flow oxygen
Antihistamines if rash
How does adrenaline treat anaphylaxis?
Causes vasoconstriction
Stimulates beta1-adrenoceptors
Reduces oedema
Bronchodilates
Attenuates further release of mediators from mast cells and basophils by nincrease c-AMP so release of inflammatory mediators is reduced
What is the clinical criteria of a drug allergy?
Does not correlate with pharmacological properties of the drug
No linear relation to dose
Reaction similar to other allergens
Disappearance on cessation and reappearance on re-exposure
Only occurs in a minority of patients on the drug
What is a confirmatory blood test for anaphylaxis?
Serum mast cell tryptase.
Peaks an hour after reaction and lasts around 6 hours
How does adrenaline treat anaphylaxis?
Has beta-adrenergic receptor activity.
Stimulation of beta1-adrenergic receptors causes positive ionotropic and chonotropic effects on the heart (increased force and rate).
Stimulation of beta2-adrenergic receptors reduce oedema and bronchodilates
What occurs when histamine receptors are stimulated?
Histamine 1 receptors mediate vasodilation, hypotension and flushing.
Histamine 2 receptors increase atrial and ventricular contractility, atrial chronotrophy and coronary artery vasodilation.
Why may leukaemia cause splenomagely?
Because the spleen removes RBCs
Define innate immune response:
Non-specific defence system that you were born with
Define adaptive immune response:
Acquired defence to destroy/prevent growth of pathogens
What are the 6 cells of the innate immune system?
Neutrophils
Natural killer cells
Macrophages
Mast cells
Eosinophils
Basophils
Briefly explain the role of neutrophils:
Most abundant WBC, phagocytic and involved in inflammation
Briefly explain the role of macrophages:
(When monocytes migrate from blood to tissue they become macrophages)
Phagocytic, antigen presenting and secrete cytokines
Briefly explain the role of basophils:
Involved in allergies
Briefly explain the role of eosinophils:
Involved in parasitic infections
Briefly explain the role of mast cells:
Involved in anaphylaxis and asthma (IgE binds to allergen which then binds to mast cells causing them to release products incl histamines)
Briefly explain the role of natural killer cells:
Release Lytic granules that kill cells infected with virus
What are the main antigen presenting cells?
Dendritic cells§
What are the cells of the adaptive immune system?
T cells: T helper cells and cytotoxic T cells
B cells
What proteins do the different types of T cell present?
T helper cells: CD4
Cytotoxic T cells: CD8
What is the role of T helper cells?
Express CD4
Activate B cells and cytotoxic T cells
What is the role of cytotoxic T cels?
Express CD8
Release perforin that cause cells to lyse
What is CD20 and what’s its significance?
The mature B cell marker (protein on B cells)
Monoclonal antibodies targed CD20
Used to measure levels of B cells which may be elevated in certain B cell leukaemias
What are the 3 main roles of antibodies?
Neutralise toxins
Opsonisation of pathogens (attract phagocytes to them)
Destroy pathogens
What are the 4 main types of antibody?
IgA
IgM
IgG
IgE
What are the functions and features of antibody IgG?
It is the most abundant antibody in the blood and is highly specific
It has 4 subclasses
It can cross the placenta
What are the functions and features of antibody IgE?
It is bound to mast cells and basophils by FceR.
Important in allergy and parasite infections.
Out of IgG and IgM, whose levels increase more in a second exposure and whose increase the same as the first exposure?
IgG levels increase in second exposure
IgM levels experience the same increase as in the first exposure.
(Should be IgMore but it’s not!)
What is active vs passive immunity?
Active: immunity produced by the host immune system
Passive: immunity produced with no host participation
What are the 3 steps of acute inflammation?
- Vascular component (dilation of vessels and increased vascular permeability)
- Exudative component (leakage of protein rich fluid)
- Neutrophil polymorph (recruited to tissue)
What are the 4 stages to neutrophil polymorph recruitment in acute inflammation?
- Migration (increased plasma viscosity and slowing flow causes neutrophils to migrate to plasmatic zone)
- Adhesion (adhesion of neutrophils to endothelium within venules)
- Emigration (neutrophils pass through endothelial cells to the basal lamina and then vessel wall)
Diapedesis (some RBCs may also escape from vessels = passive transport)
Name 6 possible causes of acute inflammation:
Microbial infection (bacteria, virus)
Hypersensitivity reactions
Physical agents (trauma, heat)
Chemicals
Bacterial toxins
Tissue necrosis
Name 5 ways in which acute inflammation may appear clinically:
Rubor (Redness due to small vessel dilation)
Calor (heat peripherally)
Tumour (swelling due to oedema or mass)
Dolor (=pain)
Loss of function (due to ischaemia?)
What are 4 possible outcomes of acute inflammation?
- Resolution
- Suppuration (formation of pus -> scarring)
- Organisation (Replacement by granulation tissue)
- Progression to chronic
Define cholinergic and andrenergic:
Cholinergic= relating to acetylcholine (ACh) and its receptor
Adrenergic= relating to (nor)adrenaline and their receptors
Define commensal:
Organism which colonises (lives in) the host but causes no disease in normal circumastances
(If these move to somewhere they don’t belong they can then cause disease eg UTI)
What is an opportunist pathogen?
Microbe that only causes disease if host defence are compromised- normally don’t cause disease
Define virulence/pathogenicity:
The degree to which a given organism is pathogenic
What colour do gram positive and negative bacteria stain with gram stain?
Gram positive = purple
Gram negative = red
What in bacteria structure allows adhesion to human cells?
Pili/fimbriae
What type of bacteria do not stain with gram stain?
Mycobacteria
How can we classify mycobacteria?
Ziehl-Neelsen stain
How do gram positive and negative bacteria differ structurally?
Gram positives have: capsule, large peptidoglycan layer then an inner membrane
Gram negatives: capsule, lipopolysaccharide layer (endotoxin), outer membrane, lipoproteins, small peptidoglycan layer then inner membrane
What is the doubling time of most viruses?
Less than an hour
What is the doubling time of e.coli?
20-30 mins
What is the doubling time of mycobacterium lebrae?
2 weeks
What is a bacterial endotoxin?
Component of the outer membrane of bacteria eg a lipopolysaccharide in gram negative bacteria
What is a bacterial exotoxin?
Secreted proteins of gram positive and gram negative bacteria
What are bacterial free spores?
Spores formed inside a bacteria that are highly resistant to temperature and water
Give the composition, action, effect from heat, antigenecity and producer of exotoxins:
Composition: protein
Action: specific
Effect from heat: labile
Antigenicity: strong (bc protein)
Producer: gram positive and gram negative
Give the composition, action, effect from heat, antigenecity and producer of endotoxins:
Composition: lipipolysaccharide
Action: non-specific
Effect from heat: stable
Antigenicity: weak
Producer: only gram negative
How can bacteria transfer genetic information between each other?
Conjugation
How does genetic variation arise in bacteria?
Mutations (deletion, insertion, substitution)
Gene transfer (by transformation, transduction and conjugation)
What is antigenicity?
The ability of an antigen or foreign species to bind to something
What are the 2 major gram positive cocci?
Streptococci
Staphylococci
How do we differentiate streptococci and staphylococci microscopically?
Staphylococci tend to group in clusters
Streptococci tend to group in chains
What is osteomyelitis?
Infection in bone
How are staphylococci classified?
Do they contain a coagulase (blood clotting) enzyme or not
Are staphylococcus aureus and epidermis coagulase positive or negative?
Staphylococcus aureus= coagulase positive
Staphylococcus epidermis= coagulase negative
How is staphylococcus spread?
Aerosol and touch
What is MRSA?
Methicillin resistant staphylococcus aureus
What are the two ways in which staphylococcus aureus causes disease?
Pyogenic- via pus (wound infections, abscesses, pneumonia)
Toxin mediated (food poisoning, toxic shock)
What is different about coagulase-negative staphylococci?
They are opportunistic (only really affect immunocompromised or prosthetics or by going to a place they don’t belong)
What are two important coagulase negative staphylococci and what do they cause?
S. Epidermis= pusy skin
S. Saprophyticus= acute cystitis
What does alpha, beta and heamolytic negative streptococci mean?
Alpha- partial haemolysis on blood agar- green
Beta- complete lysis on blood agar- blue
Negative/gamma- no lysis
How do we tell what beta heamoytic streptococci we have?
Using Lancefield microbead agglutination test
Group A= s. Pyogenes
Group B= s.agalactiae
What infections are caused by S.pyogenes?
Respiratory (tonsillitis)
Skin and soft tissue (wound infections, cellulitis)
Scarlet fever
Complications incl rheumatic fever, glomerulonephritis
What particular complications can viridans groups streptococci cause?
Dental caries and abscesses
Infective endocarditis
What are the important aerobic gram positive bacilli?
Listeria monocytogenes (only causes infection in immunocompromised eg pregnant)
Bacillus anthracis (forms spores)
Corynebacterium diphtheriae (prevented by vaccine, leads to cvrs issues)
What are the important anaerobic gram positive bacilli?
= clostridia
C. Tetani = tetanus (from infected wounds -> muscle contractions and spasms)
C. Botulinum = botulism (from contaminated canned food -> paralysis)
C. Difficile = antibiotic associate diarrhoea -> pseudomembranous colitis (attacks gut enterocytes)
What are the features of clostridia (anaerobic gram positive bacilli)?
Spore forming
Produce toxins
What is the biggest difference between gram negative and positive bacteria?
Gram negative have an inner and outer layer
What is the lipopolysaccharide (LPS) of gram negative bacteria?
LPS= the outer leaflet of the outer membrane on gram negatives.
It comprises:
-lipid A= toxic portion
-core antigen
-somatic antigen (highly antigenic)
What are virulence determinants?
Any product/strategy that contributes to pathogenicity
1. Colonisation factors (adhesins, invasins, nutrient aquisition, defence against host)
2. Toxins (effectors)
What are family enterobacteriaceae?
= enterobacteria
Rods, mostly motile
Grow aerobically but can become anaerobic if necessary (eg large intestine = anaerobic)
What is MacConkey-lactose agar used for?
Selectively for testing enterobacteria
To see if they can use lactose for energy/food or not
For the following enterobacteria, can they use lactose, and are they motile?
Shigella flexneri
Escherichia coli (E. coli)
Salmonella enterica
Shigella flexneri cannot use lactose and is not motile
Escherichia coli (E. coli) can use lactose and is motile
Salmonella enterica cannot use lactose but is motile
What is the most common bacteria to cause of female UTIs?
E.coli- via faeces or catherisation
What are 6 common infections caused by E.coli strains?
Wound infections
UTIs
Gastroenteritis
Travellers’ diarrhoea
Bacteraemia (sometimes -> sepsis)
Meningitis sometimes in infants but rare
How can some e.coli strains become pathogenic?
There may be several ‘pathovars’
The core genome exists and can acquire pathogenic genes/accessory genes that cause pathogenicity
What is the difference between e.coli and shigella?
Shigella = “e.coli + virulence plasmid”
What are the 4 species of shigella bacteria, which is the most and least severe?
Dysenteriae (most severe)
Flexneri
Boydii
Sonnei (least severe)
What are the symptoms of shigella bacterial infections and how is it spread?
Frequent passage of stools
Pus and blood, cramps and fever
Spread person-to-person or though contaminated food and water
How does shigella cause the symptoms it does?
Induce their own uptake from M cells on the gut.
Induce apoptosis of macrophages which then release shigella when they die = inflammation and distraction of gut tissue
What are the two types of salmonella and which is responsible for the common infection?
S. Enterica = responsible for salmonellosis
S. Bongori= rare, from contact with reptiles
What are the 3 forms of salmonellosis (infection) caused by s.enterica?
Gastroenteritis (food poising from milk, poultry and eggs) (localised infection)
Enteric fever or typhoid fever (not localised= systemic) (from poor quality drinking water)
Bacteraemia
What is the route of salmonella from food/water to infection?
Invasion of gut epithelium
Transcytosed to basolateral membrane
Enters submucosa macrophages
Intracellular survival/replication
What is special about proteus mirabilis?
= pathogenic enterobacteria
Has surface motility= swarming
Is elongated &
Produces urease so urine pH increases, calcium phosphate precipitates making bladder/kidney stones
What are the features of klebsiella pneumoniae?
Evnironmental
Opportunistic- often seen in immunocompromised/elderly/neonates
Normally exists in gastrointestinal tract- here it is benign but can cause infections if goes elsewhere such as UTI, neurone, sepsis etc
This is multi drug resistance
What is a zoonosis?
Infection from an animal
What are the features of vibrio cholerae?
Facultative anaerobe
Curved rods with single polar flagellum
Causes cholera- most severe diarrhoeal disease
Contamination of drinking waster due to flooding/poor sanitation
Faecal-oral route not person-to-person
Causes production of very watery stool “rice water stool” = loss of fluids and electrolytes
What are the features of pseudomonas aeruginosa?
Free-living motile and rod shaped
Opportunistic
Resistant to many antibiotics and some disinfectants
How are pseudomonas aeruginose infections classified?
- Localised (burn/surgical wounds, UTIs keratitis- these are GREEN fluorescent)
- Systematic (bacteraemia -> sepsis) occurs in neutropenic patients- with low blood count
- ICU patients on ventilators/intubated (= ventilator acquired pneumonia)
All of these are opportunistic
What are the features of haemophilus influenzae incl what do they cause (5)?
Exclusively human parasites
Carried in the nasal pharynx- non capsulated strains
Opportunistic infections include:
Meningitis
Bronchopneumonia
Epiglottitism (caused by invasive strains with a capsule), sinusitis and otitis media
Bacteraemia (caused by invasive strains with a capsule)
Pneumonia in compromised patients (CF, COPD)
How do we diagnose (microscopically) haemophilus influenzae?
Heating a blood agar it gives a brown colour = chocolate agar
What are the features of legionella pneumophila?
Causes 1-3% of pneumonias
It is severe- has a 15-20% mortality
Affects the immunocompromised
Infection from man-made aquatic environments
What are the features of bordetella pertussis?
Pertussis= whooping cough
Short, sometimes oval, rods
Fastidious (complex nutritional needs to hard to grow in lab)
Low contagious dose- aerosol transmission
Humans are the only known reservoir
Non-invasive (localised)
What are the features of neisseria?
Non-flaggellated diplococci (called this because they go round in pairs)
Two major species: n.meningitidis and n.gonorrhoeae
Humans are the only known resevoir
What are the features of neisseria meningitidis?
= meningococcus
Carried asymptomatically by 5-10% of population
Person-to-person often when over populated groups of young people
What are the features of N.gonorrhoeae?
= gonococcus
Causes gonorrhoea- second most common STD worldwide
Person-to-person
Can be asymptomatic (10% of men, 50% of women)
Can lead to various itises
What are the features of campylobacter?
Spiral rods
Two common species: jejuni and coli
Unipolar or bipolar flagella
Most common cause of food poisoning (lives in guts of certain animals so if not cooked properly or pasteurised)
Symptoms incl mild to severe diarrhoea
What are the features of helicobacter pylori?
Spiral shaped, polar flagella tuft
Before this was discovered- we thought the stomach was sterile but this was found in about 50% of stomachs
Can cause gastritis and peptic ulcer disease
Can cause cancer (gastric adenocarcinoma)
What are the features of phylum bacteriodetes?
Non-motile rods
Most abundant bacteria in large intestine
Opportunistic (eg through ulcers)
Most common cause of anaerobic infections
Main one is B.Fragilis (least common but causes most infections)
What are the features of phylum chlamydiae?
Very small non-motile
Not rod shaped or spiral shaped!
Obligate intracellular parasites
Many live asymptomatically
Can only be detected by PCR or by seeing if the person has antibodies- though they could have had these for years
What is the life-cycle of chlamydia?
Unique growth cycle with 2 developmental stages:
1. Elementary Bodies (rigid) which enter cells through endocytosis. They then differentiate into…
2. Reticulate bodies (fragile) which replicate and acquire nutrients from host cell
What are the 3 important members of the Chlamydia genus?
C. Trachomatis
C. Pneumoniae
C. Psittaci
What are the strains of Chlamydia Trachomatis?
There are 3 strains:
Trachoma biovar (can lead to blindness, through eye-to-eye transmission)
Genital tract biovar (most common STD= what we know as chlamydia) (infects epithelial cells and can ascend to uterus and ovaries) (can cause conjunctivitis from hand-to-eye transmission)
Lympho granuloma venereum biovar
What are the stages of caring out a gram stain?
- Fresh culture must be used
- Dilute cells and form a thin film over the slide
- Pass slide over a Bunsen burner to make it warm (not hot!)
- Stain cells with crystal violet then rinse with water after 30-40 secs
- Add grams iodine and leave for 1 minute before rinsing
- Decolorise the cells with iodine or ethanol (dropwise with slide tilted) then wash off excess
- Cover cells with safronin and then rinse with water before drying
What are the different shapes of virus?
Helical
Isoahedral
Complex
Non-enveloped
Enveloped
What is a virus?
Infectious, obligate intracellular parasite comprising genetic material (DNA OR RNA surrounded by a protein coat and/or membrane
How do viruses replicate?
- Attachment to a specific receptor
- Cell entry: uncoating of virion within cell
- Host cell interaction + replication (migration of genome to nucleus and transcription to mRNA using host materials, translation of mRNA produces structural proteins, viral genome and non-structural proteins such as enzymes)
- Assembly of virion (= complete infectious viral particle)
- Release of new virus particles
How do viruses cause disease (5 ways) ?
- Direct distraction of host cells
- Modification of host cell
- Over-reactivity of immune system
- Damage through cell proliferation
- Evasion of host defences (at cellular level and at molecular level)
How does poliovirus cause disease?
By direct destruction of host cells
Causes lysis of Neurons -> paralysis
How does rotavirus cause disease?
By modification of host cells
Causes atrophies in villi and flatten epithelial cells to decrease small intestine surface area so fewer nutrients are absorbed
Causes hyperosmotic state
Causes profuse diarrhoea
How does hepatitis B cause disease?
By over-reactivity of immune system
Produces cytotoxic response which leads to jaundice, fever etc
How does covid 19 cause disease?
By over-activity of immune system
How does human papilloma virus cause disease and what disease does it cause?
Causes cervical cancer
By damage though cell proliferation
(Viral expression of HPV proteins + viral DNA is integrated into host chromosomes leads to dysplasia and neoplasia)
Give an example for each way viruses can cause disease?
- Direct distraction of host cells (poliovirus)
- Modification of host cell (rotavirus)
- Over-reactivity of immune system (hep B)
- Damage through cell proliferation (papilloma)
- Evasion of host defences (cellular level =herpesviridae) (molecular level = HIV, influenza)
How can viruses evade host defences?
At a molecular level -> antigenic variability, prevention of host cell apoptosis, down regulation of proteins, interference with host cell antigen processing pathways eg. HIV
What are important things to ask a mother at their 6 week post-natal check up?
Ask about their lochia (bleeding after birth)
Ask about contraception
Ask about support/partner
Ask about mental health
Ask about domestic abuse
Check for baby genital mutilation
Ask any other concerns
Do baby check
What do you do in a baby check?
Red reflex (using ophthalmoscope)
Hip dysplasia
Check ears (too low -> down’s)
Check testicular descention
Check heart
List what is screened for antenatally?
Fetal anatomy scan
Screening for down’s
Sickle cell and thalassaemia
Screening for infectious diseases
What is screened for in a newborn baby?
Physical external inspection
Hearing test
Newborn blood spot = CF, PKU, sickle cell etc
Physical examination = cardiac, hip dysplasia, eyes, testes
What is screened for at the 6 week baby check?
Physical = heart, hips, cataract, testes
Includes = weight, head circumference, appearance, tone/movement/posture, head and eyes
What is reviewed by schools for children age 5 ish years?
Height
Weight
Vision
Hearing
What is reviewed by the health visitor at 2-2.5 yrs?
General development
Growth, eating and activity
Tooth brushing/dental appointments
Behaviour
Sleep
Safety
Vaccinations
What are the ways in which we can obtain passive immunity?
(Antigens are provided directly to us)
Mostly cross-placental
Sometimes via transfusion of blood/serum
What are the types of vaccines (or things they can be made from)?
Made from inactivated virus
Attenuated live organism
Secreted products
Constituents of cell walls
Recombinant components
What is primary and secondary vaccine failure?
Primary vaccine failure= person doesn’t develop immunity
Secondary= initially responds but protection wanes over time
What are 6 examples of major vaccine preventable diseases?
Diptheria
Polio
Tetanus
Pertussis (= whooping cough)
Haemophilus influenza type B
Meningococcal disease (-> meningitis, sepsis)
What are signs of respiratory distress in babies?
Breathing very quickly (infants should breath at 30-50- more when they’re younger)
Prominent ribs and sub costal recession because diaphragm is trying so hard
What does polio do to cause disease?
Attacks the nerves causing poliomyelitis (damage to myelin)
When the nerves are damaged, the muscles begin to waste = muscle atrophy
What reasons could a disease be notifiable for?
They’re very dangerous/harmful
Very infectious and vaccine preventable
If they need specific control measures
Name the sterile sites on the body (6) ?
Blood
CSF
Joints
Lower resp tract
Pleural fluid
Peritoneal cavity
Name the sites of the body colonised with flora (bacteria) (6):
Gastrointestinal tract
Skin
Bladder
Oral cavity
Vagina
Urethra
What are the symptoms of scarlet fever?
“Sandpaper rash” = rash feels rough
“Strawberry tongue”
Think of risk settings and co-inections
Define adrenergic:
Relating to adrenaline or noradrenaline and their receptors
Define cholinergic:
Relating to acetylcholine and its receptors
What are the differences between somatic and autonomic nervous system?
Somatic= single neuron, innervates skeletal muscles, leads to excitation
Autonomic= tow neuron chain- two neurones separated by autonomic ganglion, smooth muscle & cardiac muscles & glands, leads to either excitation or inhibition
In general, what are the receptors and neuro-transmitters pre and post-ganglionic?
Preganglionic= ACh acts on NICOTINIC receptors
Postganglionic= ACh acts on MUSCARINIC receptors (parasympathetic) and NORADRENALINE acts on Alpha and Beta receptors (sympathetic)
What are the cranial nerves inner sting the parasympathetic nuclei of the brainstem?
3
7
9
10
What are the exceptions for pre and post-ganglion in neurotransmitters?
Sometimes ACh is released at sympathetic post-ganglion if terminals (eg in sweat glands)
Nitric oxide is released from parasympathetic postganglionic termini in blood vessels
What are the 5 types of muscarinic receptors?
M1: brain
M2: heart
M3: all organs with parasympathetic innervation
M4: mainly CNS
M5: mainly CNS
All found outside the cell and will activate intracellular processes though G-proteins
What are the M2 muscarinic receptors- what happens when it is activated?
On the heart sino-atrial node (pacemaker)
Activation decreases the heart rate
On the atrio-ventricular node
Decreases conduction velocity (slows down heart)
Induces AV node block (PR interval increases)
What are the M3 muscarinic receptors and what happens when they are activated?
In the resp system:
Acivation produces mucus and smooth muscle contraction (leading to bronchoconstriction)
In the GI tract:
Increases saliva production and gut motility
Stimulates biliary secretion
In the skin- only in places were SYMPathetic system releases ACh
Activation causes sweating
In the urinary system:
Activation causes contraction of detrusor muscle and relaxation of internal urethral sphincter so urination
In the eye:
Causes myosis (pupil constriction)
Causes increased drainage of aqueous humours and secretion of tears
What does activation of M3 muscarinic receptors in the respiratory system do?
Acivation produces mucus and smooth muscle contraction (leading to bronchoconstriction)
What does activation of M3 muscarinic receptors in the GI tract do?
Increases saliva production and gut motility
Stimulates biliary secretion
What does activation of M3 muscarinic receptors in the skin do- and where in the skin are they ?
Only in places where there is sympathetic release of ACh
Causes sweating
What does activation of M3 muscarinic receptors in the urinary system do?
Contraction of detrusor muscle
Relaxation of internal urethral sphincter
= urination
What does activation of M3 muscarinic receptors in the eye cause?
Myosis (constriction of pupils)
Increased drainage of aqueous humours
Secretion of tears
What would be observed in muscarinic poisoning?
Myosis and blurred vision
Hypersalivation
Bronchoconstriction
Bradycardia/ heart block
Diarrhoea
Polyuria (too much urine)
Hyperhidrosis (excessive sweating)
What are pilocarpine eye drops, what do they target and how do they work?
They are M3 agonists (= do what M3 does)
They increase drainage of aqueous humour, reduce ocular pressure and treat closed angle glaucoma (which occur when fluid is trapped)
Also can treat dry mouth
What is hyoscine, what does it do and how?
Hyoscine is an M3 ANTAgonist
It is used in palliative care to treat respiratory secretions and symptoms of bowel obstruction
What are 4 examples of inhaled anti-muscarinics and what do they do (incl side effects)?
Tiotropium
Glycopyrronium
Umeclidinium
Aclidinium
Can result in bronchodilation
Also antagonise other M3 receptors therefore cause dry mouth, urinary retention and can worsen glaucoma
What are 3 examples of antimuscarinics?
Solifenacin = treatment for overactive bladder
Mebeverine = treatment for irritable bowel syndrome (by slowing contractility)
What happens as a result of blocked ACh transmission outside the autonomic nervous system?
Skeletal muscle weakness
What is myaesthenia gravies?
Disease where ACh receptor antibodies are present and bind to ACh receptors (at neuromuscular junction)
Causes skeletal muscle weakness so fatigue on attempts at repeated movement
It can be treated by anti-cholinersterses which block the breakdown of ACh so there is more available at the NM junction
What are catecholamines?
A group of chemicals= neurotransmitters
One of them is noradrenaline
Important in stress response
What is noradrenaline and how does it differ from adrenaline?
Noradrenaline is released from sympathetic nerve fibre ends
Adrenaline is released from adrenal glands
What is dopamine (in context of adrenaline and noradrenaline)?
It is the precursor of Nora/adrenaline
(Chemical precursor- they have similar structures apart from presence of one more group)
What are the types of adrenergic receptors?
Alpha 1
Alpha 2
Beta 1
Beta 2
Beta 3
What are the consequences of activation of alpha 1 adrenergic receptors?
Contracts smooth muscle (pupils and blood vessels)
What are the consequences of activation of alpha 2 adrenergic receptors?
Mixed effects on smooth muscle
What are the consequences of activation of beta 1 adrenergic receptors?
Chronotropic and ionotropic effects on heart
Define chonotropic:
Effects heart rate
Define ionotropic effect on heart :
Effects strength/ power of heart beat
What are the consequences of activation of beta 2 adrenergic receptors?
Relax smooth muscle (in premature labour and asthma)
What are the consequences of activation of beta 3 adrenergic receptors?
Enhance lipolysis
Relax detrusor muscle of bladder
What is the mechanism behind consequences of alpha 1 adrenergic receptor activation?
Increases intracellular Ca2+
What is the mechanism behind consequences of alpha 2 adrenergic receptor activation?
Inhibition of cAMP generation
What do alpha 1 adrenergic receptor antagonists do and how?
Lower blood pressure by blocking alpha 1
Treating phaeochromocytoma (catecholamines secreting tumours)
Blocking alpha 1 receptors in the prostate for benign prostatic hypertrophy
What do medications that block beta 1 adrenergic receptors do?
Reduce heart rate
Reduce stroke volume
Reduce myocardial oxygen demand eg. In post-myocardial infarction
What are the main targets of beta 1 adrenergic receptors and what does activation do?
Main targets:
Heart
Kidney
Fat cells
Activation leads to:
Tachycardia
Increased stroke volume
Renin release
Lipolysis and hyperglycaemia
What are the areas where beta 2 adrenergic receptors are present and what do they cause on activation?
Bronchi: bronchodilation
Bladder wall: inhibiting micturition
Uterus: inhibition of labour
Skeletal muscle: increase contraction speed (-> tremor)
Pancreas: insulin and glucagon secretion
How does glucagon treat beta-blocker poisoning?
It increases heart rate and myocardial contractility but bypasses the beta-adrenergic receptor site therefore acts irrespective of the presence of beta-receptor blockers
What does salbutamol block?
Beta 2 adrenergic receptors
What are the macroscopic ways in which chronic inflammation can appear?
Chronic ulcer
Chronic abscess cavit
Granulomatous inflammation
Fibrosis
What are the 4 possible causes of chronic inflammation?
Primary -> chronic
Primary granulomatous disease
Transplant rejection
Primary chronic inflammation (due to autoimmune conditions, endo/exogenous materials or resistance to infective agents)
What are the cells involved in acute inflammation?
Neutrophils
Monocytes
What are the cells involved in chronic inflammation?
Lymphocytes
Macrophages
Plasma cells
What are the macroscopic features of acute inflammation?
Redness
Heat
Swelling
Pain
Loss of funtion
What is a histological hallmark of acute inflammation?
Neutrophil extravasation (leakage from vein into tissues)
What are the histological hallmarks of chronic inflammation?
Cellular infiltrate of lymphocytes, macrophages and plasma cells
Possible granulomas?
What are 6 possible causes of acute inflammation?
Microbial infections
Hypersensitivity
Tissue necrosis
Chemicals
Physical agents
Bacterial toxins
What are the 6 possible causes of chronic inflammation?
Resistance of infective agent
Endogenous/exogenous materials
Autoimmune conditions
Primary granulomatous diseases
(Above are all for primary chronic inflammation)
Transplant rejection
Progression from acute
What are the differences between arterial and venous thrombi?
Arterial thrombi are cold, painful and pale. They are commonly caused by atheroma and can cause a myocardial infarction and/or stroke
Venous thrombi are tender, red and swollen and are commonly caused by stasis across valves. They can cause DVTs and pulmonary embolisms
What is the difference between arterial and venous emboli?
Arterial emboli travel downstream to the heart/brain/peripheries (causing attack/stroke/gangrene)
Gangrene= tissue dies cos of no blood
Venous emboli travel to the vena cava and cause pulmonary embolisms. The size of the emboli will determine its impact
What are the 5 types of cell growth (and their definitions)?
Hypertrophy (increase in size of cells)
Hyperplasia (increase in number of cells)
Atrophy (decrease in cell side and/or number)
Metaplasia (change from one fully differentiated type of cell to another)
Dysplasia (morphological change seen in progression to cancer)
What are the 2 types of cell death (and their definitions)?
Apoptosis = programmed death
Necrosis = unprogrammed (due to adverse event incl infarction, burn, trauma) (followed by acute inflammation)
Do benign or malignant tumours grow inwards (endophytic) or outwards (exophytic)?
Malignant = endophytic
Benign = exophytic
What are the histological grades of tumours?
Grade 1 = well differentiated (closely resembles parent tissue)
Grade 2 = moderately differentiated
Grade 3 = poorly differentiated
What is TNM tumour staging?
Within each of the following there are stages:
T= primary tumour
N= lymph node status
M= metastatic status
What are the different T stages of TMN tumour staging?
T1: less than 3cm
T2: greater than 3cm
T3: any size tumour but is near airway or has spread locally to chest wall/diaphragm
T4: any size tumour but is located within airway or invited local structure incl heart/esophagus
What are the stages of N tumour staging in TMN?
N0: no lymph nodes are affected
N1: tumour spread to nearby nodes on the same side of the body
N2: tumour has spread to nodes further away but on the same side
N3: cancer cells present in the lymph nodes on the other side of the tumour- or in nodes near the collar/neck
What are the M stages of TNM tumour staging?
M0: mo metastases
M1: metastases
What is the varicella zoster virus and what does it cause?
VZV= one virus causes 2 diseases:
Chicken pox= primary infection
Shingles (herpes zoster)= secondary reactivation
At what time is chickenpox at its most infectious?
At day 0
(There is 1 to 3 week incubation period before the rash starts on day 0)
What groups of people are most likely to be seriously affected by chickenpox?
Immunocompromised/patients who have had transplants
Adults
Pregnant women
Smokers
What is the ‘evolution’ of chickenpox lesions?
Macula to papule to vesicle to postule to crust
What are the main differences of clinical presentations in chickenpox and smallpox?
Smallpox affects peripheries
Chickenpox affects central parts of the body
What information needs to be collected when seeing someone with chickenpox?
Age of the patient
Onset of the rash
Any contacts
Immune suppressed?
Pregnant?
What are possible complications of chicken pox?
Dehydration
Haemorrhagic change
Cerebellar ataxia (common) = poor muscle control
Encephalitis (may present as confusion)
Varicella pneumonia (= chicken pox specific pneumonia)
Bacteria empyema (pockets of pus collected inside body cavities)
Skin and soft tissue infection
Deep sepsis?
Congenital varicella syndrome (in babies of pregnant mothers)
What is the mortality rate in treated chickenpox?
6%
What are the symptoms of foetal varicella syndrome?
It occurs in 10-15% of cases of chickenpox in pregnancy
Usually is asymptomatic but if there are manifestations they will have shingles in their first year of life
It can cause severe defects including skin scarring, limb hypoplasia (poorly developed limbs), visceral and ocular lesions and microcephalic/growth retardation
What is viral dormancy and why is it important?
The ability of a virus to lie dormant (not doing anything) within a body.
It is important because they can ‘wake up’ when/if the body goes though a period of lower immunity eg. Chemotherapy
For example- chicknpox virus can be dormant then come back and travel along the same sensory nerve to the same patch of skin it once was in- and come back as shingles. (Therefore a rash on one side of the body at a place supplied by one nerve root is commonly shingles).
How do shingles and chickenpox differ?
Chickenpox develops slowly and has distinctive stages where lesions look different whereas shingles comes on rapidly and therefore you cannot visualise the stages of development.
Shingles is most common in the elderly compared to chickenpox in children.
What are the features of shingles?
More present in the thoracic region and less frequently in the cervical, lumbar and sacral dermatomes.
10-20% of cases are opthalmic (dangerous affects opthalmic division of trigeminal nerve)
Very painful as nerve is irritated.
What is the cause of a haemorragic rash and what does it appear like clinically?
There’s bleeding in to the skin
The rash will not blanch under pressure (disappear)
What are important viruses to look for when we see rashes?
Enterovirsus (rash on hand, foot and mouth)
Parovirus (red cheeks- doesn’t normally make children majorly ill) (interacts with bone marrow and cause anaemia
Vesicular rashes (such as herpes- causing rash on the boundary between lip and skin)
Mucositis (shedding epithelium from inside of mouth= left a place for bugs to enter)
What are the histological appearances of cytomegalovirus infection?
Atypical lymphocytes (larger, sticking to red blood cells)
What is worrying about cytomegalovirus re-infection?
When it comes back in patients with immunodeficiency (who have become immunosupressed)
When it comes back, it is very different from the first infection.
Causes a ‘pizza pan retina’ which is sight affecting (inflammation looks like soft cheese and blood looks like tomato)
What are the symptoms of measles?
=CCDC
Cough
Coryza (inflammation of mucosal membrane incl in nose)
Diarrhoea
Control (immune control- report it!)
What are protazoa?
Eukaryotes
Single called with a nucleas
= one celled animals
What are the 5 major groups of protazoa, and how are they grouped?
Flagellates: have tails
Amoebae: use finger like projections to pull themselves along
Microsporidia: tiny and not very mobile
Sporozoa: one called non-motile
Ciliates: have cillia that push them along
What are important diseases caused by flaggelates?
African tyrpanosomiasis
American tyrpanosomiasis
Leishmaniasis
Trichomonas vaginalis
Gardiasis
What are the features of African tyrpanosomiasis (flagellate protazoa)?
= sleeping sickness
Chancre (hard ulcer/sore)
Flu like symptoms
CNS involvement: sleepy, confusion, personality change
Coma and death!
Diagnosed by blood film
What are the features of American tyrpanosomiasis (flagellate protazoa)?
= Chagas’ disease
Transmitted by triatomine bug (faeces entering via bite)
Causes acute flu like symptoms
Causes chronic cardiomyopathy, megaoesophagus, megacolon
What are the features of leishmaniasis (flaggelate protazoa)?
Spread by bite of sandfly
More than 20 human species
3 clinical species:
- cutaneous (not too troublesome- only a bad bite and maybe a scar)
- mucocutaneous (effects nose and pharynx- destructive lesions= social rejection)
- visceral (massive splenomegaly, hepatomegaly, high fatality without treatment, fever, weight loss and anaemia)
What are the features of trichomonas vaginalis (flagellate protazoa)?
Sexually transmitted
Asymptomatic/ dysuria (painful/difficult urination), yellow frothy discharge
= treated with metronidazole
What are the featured of giardiasis (flagellate protazoa)?
Diarrhoea
Cramps, bloating, flatulance
Recent travel
Trophozoites/cysts seen in stool
Treated with metronidazole!
What are the features of amboebiasis?
Foeco-oral spread
Caused dysentery (bloody diarrhoea), colitis, liver and lung abscesses
Trophozites/cysts can be seen in stool
Treated with metronidazole!!!
What are the major sporazoa protazoa diseases that we need to know?
Cryptosporidiosis
Toxoplasmosis
What are the features of cryptosporidiosis (sporozoa protazoa)?
Waterborne
Causes diarrhoea (watery with no blood)
Vomiting, fever and weight loss
Oocytes seen in stool
Usually seen in the severe immunocompromised
What are the features of toxoplasmosis (sporozoa protazoa)?
Contaminated food and water (with feline/cat faeces)
Only really causes issues with pregnant women or reactivation from immune compromising.
In these cases may cause toxoplasma encephalitis and/or chorioretinitis (may affect vision)
What factors should immediately make you consider malaria as a diagnosis?
Fever
Recent travel
What 5 specials transmit malaria and which is the particular concern?
PLASMODIUM FALCIPARUM = most prevalent and most deadly
Plasmodium ovale
Plasmodium vivax
Plasmodium malariae
Plasmodium knowlesi
What are the signs/symptoms of malaria?
FEVER
Chills/headache/vomiting/diarrhoea
Anaemia, jaundice, hepatosplenomegaly
“Black water fever” = dark dark urine because haemoglobin escapes
What are the stages of malaria development?
Mosquito stage
Human liver stage
Human blood stages
Define antibiotic:
Agents produced by micro-organisms that kill or inhibit the growth of bacterias in high-dilution
= work by binding to a target site on a bacteria
What factors need to be considered when deciding if an antibiotic is safe to give?
Intolerance/allergy/anaphylaxis
Side effects
Age
Renal and liver function
Pregnancy and breast feeding
Drug interactions
Risk of clostridium difficile (where normal GI flora is taken over by clostridium difficile- causes diarrhoea and GI issues)
Where do beta-lactate antibiotics act?
On the cell wall (peptidoglycan)
What are some examples of beta-lactams?
Penicillin V
Benzylpenicillinn
Flucloxacillin
Amoxicillin
+cephalopsporins
What are the 4 cephalosporins?
Cephalexin
Cefuroxime
Cetriaxone
Ceftotaxime
When are beta-lactate used?
For gram-positives
They have a thick cell wall- so we need a “cell wall weapon”
Eg. Strep, staphylo
What antibiotic will treat S.aureus and a foot infection from lancefield groups A, C and G?
Flucloxacillin
What antibiotic will treat tonsillitis or pharyngitis from Group A,C and G strep?
Oral penicillin V
IV benzylpencillin
What antibiotic will treat s.pneumoniae?
Oral (PO) amoxicillin
IV benzylpencillin
What does MRSA stand for
Methicillin-resistant staphylococcus aureus
What are glycopeptide antibiotics (give 2 examples)?
Vancomycin
Teicoplanin
They are ‘cell wall weapon’ antibiotics
Used when someone has a penicillin allergy
When can glycopeptide antibiotics be used?
For gram-positives ONLY
For those that are resistent to beta-lactase eg. MRSA or when there is allergy to penicillin
What are macrolide antibiotics and when are they used?
They are antibiotics that interfere with protein synthesis
Treat gram-positives and atypical pneumonia pathogens
Used in penicillin allergy and severe pneumonia
What are lincosamides and when are they used (+ give an EG)?
Antibiotics interfere with protein synthesis
Eg. Clinamycin
Act on gram-positives
Used in cellulitis (if allergic to penicillin) and in necrotising faciilitis?????
What infections to gram negatives commonly cause?
GI infections
UTIs
Diarrhoea causing infections
What are aminoglycoside antibiotics and what do they treat?
Antibiotic that acts on protein synthesis
= act on gram negatives and staphs
Treat UTIs and infective endocarditis
Why is meropenem special/restricted?
It needs to be used to treat the most at risk/ most sick people
Treats resistant gram negatives in immunocompromised
Has a broad activity
What are quinolone antibiotics and what to they treat?
Antibiotics that act on DNA synthesis
Act on gram negatives much more than gram positives
Used when there is a penicillin allergy to treat UTIs and intra-abdominal infections
What are trimethoprim and nitroturantoin antibiotics and what do they treat?
Both treat UTIs
Both are broad but trimethoprim is mainly used for gram negatives
What is different about the following beta-lactams?
Amoxicillin-clavulanate
Piperacillin-tazobactam
They also have beta-lactamase inhibitors
So inhibit the proteins made by gram negatives
What is co-amoxiclav antibiotic and what does it treat?
=augentim
Treats staph.aureus, streps, enterococci, gram negatives and anearobes
Is used to treat aspiration pneumonia, severe community-acquired pneumonia or more resistant urinary pathogens
What are cefuroxime antibiotics and what do they treat?
Antibiotics that treat gram positives and negatives (but not pseudomonas, anaerobes and enterococci)
Used in some surgical prophylaxis, abdominal infections and non-severe penicillin allergy
What are CPEs?
Carbapenemase producing enterobacteriaiseae
= resistant to antibiotics (Carbapenems are one of the broadest spectrum antibiotics available)
what is norovirus?
“Vomiting bug”
High attack rates among lose contacts (low infecting dose)
Has short lived immunity only
Is relatively resistant to conventional cleaning- alcohol gel isn’t really enough
= very common in hospitals
What is clostridium difficile?
A stomach bug that lays dormant in the stomach but when it ‘awakes’ it releases toxins that cause a toxic megacolon
= prolonged hospital stays
Must wash hands thoroughly- alcohol gel isn’t really enough
What are endogenous infections and how do they happen?
= Caused by patients’ own bacterial flora
Commonly happens from cannulas
The infection can spread down the line of cannulas/trachiostomy
What can we do to prevent endogenous infections?
Good nutrition and hydration
Antisepsis/skin prep
Good theatre practice
Remove lines and catheters as soon as clinically possible
Change from IV to oral treatment as soon as possible
What happens in the mosquito stage of the mosquito lifecycle?
Mosquito has a blood meal and ingests gametocytes of malaria- these mature and fuse in the gut
(They fuse to form a macrogametocyte, then an ookinete, then an oocyte)
The oocytes release sporozoites into salivary glands which are injected into the human host next time the mosquito feeds
What happens in the human stage of the mosquito lifecycle?
Mosquito injects sporozoites into the human host- they migrate to liver cells and proliferate here
These injected cells= schizont cells
Schizont bursts and ruptures into the blood stream so the schizont offspring enter the blood
What happens in the blood stage of a mosquito lifecycle?
The schizont offspring enter the blood (after bursting into the blood stream) and enter a cycle of infecting red blood cells, proliferating in them and bursting out of them.
Not all cells enter this cycle- some become gematocytes and get eaten by mosquitos to continue the life cycle.
Why is p.falciparum a particularly deadly type of malaria?
It causes obstructed microcirculation
When RBCs are infected by this type of malaria, they display to macrophages that they have a pathogen inside them and they become sticky
The infected RBCs stick to the endothelium where they roll on it, stick (in situ rosetting) and eventually cause vascular occlusion
Which particular types of malaria form hypozoites and what are these?
P.ovale and p.vivax
The hypozoites don’t all initially escape- some remain and cause a relapse months or years later
What are 3 ways that antibiotics work?
By interfering with any of the following bacterial processes:
Cell wall synthesis
Nuclei acid synthesis
Protein synthesis
What are the main group of anti-biotics which affect cell wall synthesis?
Beta-lactams
What are the groups of antibiotics that affect cell wall synthesis?
Beta lactams (incl penicillin and cephalosporins)
Carbapenems
Monobactams
Glycopeptides
How do beta lactam antibodies work?
Disrupt peptidoglycan (cell wall) production by binding covalently and irreversibly to the penicillin binding proteins
= cell wall is disrupted= lysis =hypo-osmosis environment= bacteria destroyed
Why are beta lactams more effective against gram positive bacteria than gram negative?
Gram negatives have an additional lipopolysaccharide layer that decreases antibiotic penetration
What are the main antibiotics that affect nucleic acid synthesis?
Metronidazole
Rifampicin
Fluroquinolones
What are the possible ways in which antibiotics may affect nucleic acid synthesis?
By inhibition DNA gyrase (catalyses supercooling of double stranded DNA in bacteria)
By inhibition of DNA polymerase (eg. Rifampin)
How my antibiotics affect protein synthesis in bacteria?
By affecting the ribosomes:
Either the 50S subunit or the 30S subunit
What are the ways in which bacteria ‘cause damage’?
Directly: destroy phagocytes or the cells in which bacteria replicate
Indirectly: inflammation (eg. Necrotic cells), immune pathology
By releasing toxins: exotoxins (proteins) and endotoxins (gram negative)
Diarrhoea- by bacteria damaging the gut by trying to ‘clear’ the gut
What is the difference between bactericidal and bacteriostatic?
Bectericidal= kills bacteria
Becteriostatic= suppresses growth/multiplication of bacteria
What is antibiotic MIC?
Minimum inhibitory concentration
(Lowest conc where bacterial growth is inhibited)
What are two factors that determine the efficacy of an antibiotic?
The ability to bind to enough target sites so that enough damage is done
The ability to remain at the binding site for long enough so that enough damage is done
= concentration and time
What are the goals of medicines optimisation?
It is about ensuring medicines deliver a value (financially and to the patient)
Ensuing safety and reducing wastage
Avoiding taking unnecessary medicines
What is medicine adherence?
= no longer compliance (as this removes the patient’s opinion or desire)
Adherence acknowledges the doctor’s “orders” and the patient’s beliefs
What are some examples of non adherence to prescribed medicines?
Not taking
Taking incorrect dose
Taking more or less often
Stopping prematurely
Modifying treatment to accommodate for other things
Continuing with behaviours against medical advice (eg smoking, diet)
What may be some reasons for patient non-adherence?
Practical barriers (unintentional) eg. Misunderstanding, problems using the treatment, inability to pay and forgetting
Intentional/motivational barriers incl patient beliefs and personal preferences
What is the UNAIDS 90/90/90 target?
90% of people with HIV to be diagnosed
90% of people diagnosed to be on ART (antiretroviral therapy)
90% of those on ART to have viral supression
What are the transmission routes of HIV?
Sexual
Vertical
Blood
What does U=U mean with regards to HIV?
Undetectable = Untransmittable
What is PreP ?
= pre-exposure prophylaxis of HIV
In what scenarios would you test someone for HIV?
When a clinician has indicated that a person needs testing
Routine screening in high prevalence locations
Antenatal screening
Screening in high risk groups
Patient initiated requests for screening
What is HIV POCT?
Point of care tests for HIV
= finger prick blood
= immediate result
= lower sensitivity and specificity (produces false positives and false negatives)
= lower incubation period
What are retro-viruses?
Viruses that use reverse transcriptase to make a DNA copy of themselves to be incorporated into the host genome
What is the mechanism of HIV?
Viral envelope has a high affinity for CD4
Attaches to CD4 and enters the cell via a chemokine receptor (CCR5 on first infection and CXCR4 later)
Uses reverse transcriptase to produce DNA which enters the nucleus
New viral contents is made by the cell
What are the most ‘powerful’ anti-HIV drugs?
Integrase inhibitors
What are the general trends of clinical features of untreated HIV-1 infection?
In general, when the CD4 count is higher, there are infections such as vaginal/oral candidiasis, skin disease, fatigue and pneumonia
As the CD4 count reduces, there are infections such as herpes, leukoplakia, thrush, lymphoma and CMV (herpes)
What are the key features of HIV pathogenesis?
HIV is integrated into the DNA of infected CD4-expressing cells (mostly helper T cells)
The number of infected cells in the blood does not correlate to the extent of immune supression
Immune system is constantly activated by HIV which drives pathogenesis
What are the features of the immune response to HIV?
Very vigorous but with no demonstrable protective immunity (though rare exceptions)
Excessive immune activation which actually favours viral replication
Ongoing viral replication + immunological impairment leads to clinical signs of immunodeficiency
Why are people with HIV still at a lower life expectancy even on cART?
Issues of adherence and side effects and resistance
They seem to develop ‘old age’ related illnesses at a young age such as Cv disease, lung disease etc
Why must someone with HIV take cART forever?
There always persists a resevoir of infected cells- these will start to replicate again within weeks of cessation of therapy
What is the ‘shock and kill’ strategy to ‘curing’ HIV?
The idea is to wake up the latent virus (which remains as a reservoir during treatment) the immediately after, overwhelm with ART to try and wipe out the viral reservoir
What are the 2 marker used to monitor HIV infection?
HIV viral load
CD4 count
What are some of the non-specific symptoms that someone with HIV with a low CD4 count may have?
Reactivation of varicella voster virus at the dorsal roots (chicken pox-> shingles)
Oral thrush
Oral hairy leukoplakia (white areas on the tongue which cannot be scraped off - from EBV)
Molluscum contagiosum (pox virus popular in kids but rare in adults and normally due to HIV)
What is pneumocystis pneumonia? (PCP)
Fungal pneumonia (pneumocystis jirovecci) where oxygen levels drop during/after exercise
Does not cause illness unless there is immunodeficiency
Can be treated by co-trimoxazole (weird because this is an antibiotic
What is a normal CD4 count?
From 500-1500 cells/mm^3
what does it mean if someone has TB and HIV?
They have AIDS
TB in HIV = AIDS defining
What is HAART? (In context of HIV)
= highly active anti-retroviral therapy
You usually give 3 antiretroviral drugs (two NRTIs and one other) which act on different point of the replication cycle
Define endocrine and exocrine?
Endo= glands secrete into the blood
Exo= grands secrete through a duct to the site of action
Define paracrine
Hormone action on adjacent cells
Define autocrine
Hormone action on the same cells as where they’re secreted
How do water-soluble and fat-soluble hormones differ?
Water soluble hormones travel unbound and bind to surface receptors on cells
Fat soluble hormones are protein-bound anddiffuse into cells
What are the 4 hormone classes?
Peptides
Amines
Iodothryonines
Cholesterol derrivatives and steroids
How do peptide/monoamine hormones and steroid hormones differ in their storage/production?
Steroid hormones are synthesised on demand, peptides and monoamine hormones are stored in vesicles
What are the features of peptide hormones?
Vary in length, in linear or ring structures
Stored in secretory granules, are hydrophilic
They are released in pulses or bursts and cleared by tissue or circulating enzymes
What are the stages of peptide hormone synthesis/secretion?
Synthesis from preprohormone to prohormone
Packaging from prohormone to hormone (stored as hormone and secreted as hormone)
What are the iodothyronines?
Thyroid hormones
What are the features of iodothyronine hormones?
= thyroid hormones
Protein bound
Conjugation of iodothyrosines give rise to T3 and T4
What are examples of cholesterol derivative/steroid hormones?
Vit D
Adrenocorticoids and gonadal steroids
What are the features of vitamin D?
Fat soluble
Enters cell directly into the nucleus to stimulate mRNA production
Transported via vitamin D binding protein
How do adrenocortical and gonadal steroid hormones work?
Enter cell passing to nucleus to induce a response (altered into the active metabolite and bind to a cytoplasmic receptor)
What is the intracellular pathway of steroid hormones?
Diffuse through membrane
Bind to receptor
Receptor-hormone complex enters nucleus
Receptor-hormone complex binds to GRE
This binding initiates transcription of gene to mRNA
mRNA directs protein synthesis
What are 3 possible stimuli for hormone release?
Humoral stimuli= release caused by altered levels in blood
Neural stimuli= release caused by neural input
Hormonal stimuli= release caused by another hormone
What are 5 controls of hormone action?
Hormone metabolism (removal)
Hormone receptor induction (so therefore hormone can now work)
Hormone receptor down regulation (so now hormone can’t work)
Synergism (combined effects of two hormones is bigger than the sum)
Antagonism
What are the hormones of the posterior pituitary?
Oxytocin
ADH
What is the mechanism of ADH and oxytocin release?
Hypothalamic neurons synthesise oxytocin and ADH, they are transported down the axons of the hypothalamic-hypophyseal tract to the posterior pituitary
What are the controls of ADH/vasopressin release?
Increased by:
High osmolality and low blood volume
Nausea, vomiting, stress and exersice
Reduced by Caffeine, alcohol
What are the hormones of the anterior pituitary, what do they all have in common?
TSH
ACTH
FSH
LH
GHRH
PRL
These all stimulate the release of hormones from the hypothalamus
What are the presentation of pituitary dysfunction?
Tumour mess effects (vision loss from optic chaism, headaches etc)
Hormone excess
Hormone deficiency
What are the functions of thyroid hormone?
Accelerate food metabolism
Increases protein synthesis
Stimulation of carb metabolism
Enhances fat metabolism
Increases ventilation rate
Increases cardiac output and heart rate
Brain development
Increased growth rate
What does leptin do?
Switches off the appetite
People who are leptin deficient are often very obese, hyperinsulinaemic
What is Ghrelin?
Stimulate appetite and growth hormone release
High levels in blood during fasting
What are the clinical presentations of POMC deficiency?
Pale skin
Central obesity
What are the actions of peptide YY?
Secreted in response to food
Inhibits gastric motility
Reduces appetite
What are the types of appetite stimulators?
Olfactory
Gustatory
Cognitive
Visual
What hormones are released in order to increase satiety and stop feeding?
CCK
GLP (glucose dependent glucagon)
Insulin
PYY
(leptin in the long term)
What is a suppository?
A drug administered by mucosal absorption
What are the two main dependencies for antibiotics?
Time and concentration
(Time dependant antibiotics need to be given regularly at shorter intervals)
(Concentration dependant antibiotics need to be given in larger doses at less regular intervals)
What are the 4 mechanisms by which bacteria resist antibiotics?
Change the antibiotic target (stop from binding from binding to itself and make bind to something else)
Destroy antibiotic (by some enzyme process)
Prevent antibiotic access (by modifying number/size/selectivity of membrane channels)
Remove antibiotic from bacteria (pump out once it’s already in)
By what mechanism does MRSA have resistance?
Flucloxacillin (methicillin) can no longer bind to staphylococcus aureus because the target has changed shape
What is acquired vs intrinsic antibiotic resistence?
Intrinsic= naturally resistant (so all sub populations will be equally resistant)
Acquired= due to spontaneous gene mutation or horizontal gene transfer (3 ways)
What are the 3 ways in which horizontal gene transfer occurs in bacteria?
Transduction (mediated by bacteriophages which parakeet the DNA from one to another)
Conjugation (a sex pills forms between two cells and a plasmid is transferred) = most concerning
Transformation (take up free DNA from the environment and incorporate it into their chromosome)
What are the important gram positive resistant bacteria and how do they work?
MRSA (methicillin/Flucloxacillin resistant staphylococcus aureus)
=bacteriophage mediated transduction
VRA (vancomycin resistant enterococci)
= plasmid mediated
What is the important gram negative resistant bacteria and how does it work?
ESBL (extended spectrum beta lactamase)
= hydrolyse oxyimino sites of different antibiotics
What are HEU infants?
HIV exposed uninfected infants
What are common complications of perinatal HIV?
Heart muscle abnormalities (in 20%)
Chronic lung disease (in 30%)
Growth stunting (30-50%)
For what reason/s is an HIV-1 vaccine very hard to develop?
There are multiple variants of HIV-1
There are multiple routes of aquisition
When we first treat HIV what should we see in the viral load and CD4 count?
Viral load should immediately drop
DC4 count should slowly rise again but in some people it never does/does very late or slowly
What is the most common opportunistic infection in HIV?
PCP
= pneumocystis pneumonia
Fungal pneumonia
What features make an anaesthetic drug more/less fast acting?
Being lipid soluble means that a drug can cross the blood brain barrier more quickly
Being protein bound means there will be a lower concentration of the drug in the plasma making a slower delivery
How is morphine metabolised?
Morphine is metabolised in the liver to morphine-6-glucoronide which is more potent than morphine
It is excreted in the kidney
What dose of morphine is used for intramuscular vs oral and why?
Double orally compared to IM
This is because morphine is is taken into the liver immediately after enteric absorption and metabolised into an inactive compound before entering circulation
In the fasting state where (and how) does glucose come from?
From the liver (sometimes kidney) from the breakdown of glucose or from gluconeogenesis
What is the mechanism of insulin secretion in beta cells?
Glucose enters via GLUT2
Glucose is phosphorylated by glucokinase (generating ATP which closes KATP channels so the membrane is depolarised)
Calcium then comes in to the cell
Calcium stimulates the secretion of insulin
What is the mechanism of action for insulin on muscle and fat cells?
Insulin stimulates insulin receptor
…signalling cascade…
GLUT4 transporters travel to the membrane enabling glucose to enter the cell
In which ways does diabetes cause morbidity/mortality?
Acute hyperglycaemia leads to acute metabolic emergencies: diabetic ketoacidosis (and hyperosmolar coma rare and only in type 2)
Chronic hyperglycaemia leading to tissue complications
Side effects of treatment (hyPOglycaemia)
What is an eye complication associated with diabetes?
Diabetic retinopathy
What is an brain complication associated with diabetes?
Stroke
What is an heart complication associated with diabetes?
Cardiovascular disease
What is an nervous complication associated with diabetes?
Diabetic neuropathy
What is an renal complication associated with diabetes?
Diabetic nephropathy (-> end stage renal disease)
What are the types of diabetes?
Type 1
Type 2 (incl gestational and medication induced)
MODY (maturity inset diabetes of youth)= monogenic diabetes
Pancreatic diabetes (caused by recurrent pancreatitis causing damage to beta cells)
Endocrine diabetes (secondary to excessive secretion of growth hormone in acromegaly, or steroids in cushing’s)
Malnutrition related diabetes
What clinical tests determine diabetes?
Alongside symptoms:
Random plasma glucose > 11mmol/l
Fasting plasma glucose >7mmol/l (normal is less than 4)
No symptoms:
GTT (glucose tolerance test)
Measure HbA1c > 48mmol/mol (measures how much glucose is attached to haemoglobin)
How is type 1 diabetes characterised?
Insulin deficiency disease characterised by loss of beta cells due to autoimmune destruction
What is the mechanism behind type 1 diabetes?
Beta cells are lost because they express antigens of HLA histocompatability system- may be in response to environment? We don’t know?
This activates a chronic cell mediated immune process leading to chronic insulin deficiency
What causes type 2 diabetes?
Genes + environment lead to 2 main defects:
Impaired insulin secretion
Insulin resistance!!!
In some order: insulin demand is very high because it is not working, leads to progressive hyperglycaemia and high free fatty acids
How is the history of type 1 and type 2 diabetes different?
Type 2 diabetes has a history of years of impaired glucose tolerance before clinical symptoms show, they may appear with microvascular and macro vascular complications which wouldn’t be seen in type 1.
What is the significance of insulin levels in type 2 diabetes?
Insulin levels are ALWAYS detectable
Because of this people with type 2 diabetes do not lose weight as they do not suffer from muscle catabolism
What is seen in the urine of people with type 1 and type 2 diabetes?
In type 1: glucose and ketones
In type 2: glucose
What is the effect on muscle in type 1 vs type 2 diabetes?
In type 1: muscle/fat breakdown
In type 2: no muscle/fat breakdown
What are 2 the main treatments for type 2 diabetes?
Sulphonylureas (incl gliclazide and glibenclamide)
Thiazolidinediones
How do sulphonylureas work to treat type 2 diabetes?
Stimulate insulin release by binding to beta cell receptors
But this is at the expense of significant weight gain and does not prevent the gradual failure of insulin secretion
Can also cause prolonged hypoglycaemia especially when renal function is impaired
How to thiazolidinediones work to treat type 2 diabetes?
Bind to receptors in adipose tissue and activate genes concerned with glucose uptake and utilisation
This improves insulin sensitivity but they increase weight and risk of heart failure
What is GLP-1 and what does it do?
A protein secreted from L cells in the intestine
It slows gastric emptying, stimulates insulin secretion and suppresses glucagon secretion and improves beta cell funtion
(Hence improves insulin sensitivity and enhances douches disposal)
Why can we not use native GLP-1 to treat type 2 diabetes?
It is rapidly degraded by DPP-IV circulating enzyme
But can be prescribed with analogues that extend the duration of action of GLP-1
What are GLP-1 analogues (give some examples)?
They are medication for type 2 diabetes that reduce weight and lower glucose
Eg. Exanatide, liraglutide, lixisenatide
How do SGLT2 inhibitors treat type 2 diabetes?
SGLT2 is a transport protein that acts to reabsorb glucose in the kidney proximal tubules
Inhibitors of this increase glucose excretion and lower blood glucose
Eg. Empagliflozin canagliflozin
Why doesn’t diabetic ketoacidosis occur in type 2 diabetes?
It is rare because low insulin levels are sufficient to suppress catabolism and prevent ketogenesis
What is basal insulin?
The insulin that is longer active and keeps blood glucose steady for hours/in fasted state
What is bolus insulin?
Insulin that is released in the spike of glucose after feeding
Short-active
What are the levels of hypoglycaemia?
Level 3 is less severe but still serious- patient has impaired cognitive function and sufficient enough to require external help to recover
Level 2 is serious biochemical- plasma glucose of <3mmol/l
Level 1 is alert value where plasma glucose is <3.9mmol/l with no symptoms
What are the common autonomic symptoms of hypoglycaemia?
Trembling
Palpitations
Sweating
Anxiety
Hunger
Basically describe how modern insulin therapy works?
Basal and bolus insulin are separated and given at appropriate times
Blouses given pre meal based on the carb content of the food given
Basal given either twice daily or adjusted to maintain fasting blood glucose
What are the affects of hypoglycaemia on the brain?
Cognitive dysfunction
Blackouts
Seizures
Comas
Psychological effects
What are the affects of hypoglycaemia on the heart?
Increased risk of myocardial ischaemia and cardiac arrhythmias
What are the musculoskeletal affects of hypoglycaemia?
Falls, accidents, driving accidents, fractures and dislocations
What are the affects of hypoglycaemia on the circulation?
Inflammation, blood coagulation abnormalities, haemodynamic changes, endothelial dysfunction
What are the common neuroglycopenic symptoms (ie. Caused by shortage of glucose in the brain)?
Difficulty concentrating
Confusion
Weakness
Drowsiness, dizziness
Vision changes
Difficulty speaking
What are the 6 most common causes/risk factors for hypoglycaemia?
Having diabetes for a long time (at the beginning of type 1 there remains some insulin and glucagon levels but these diminish years of having diabetes go on)
Tight glycemic control with repeated episodes of non-severe hypoglycaemia
Increasing age (as body responses are slower)
Increased physical activity
Sleeping
Use of drugs and alcohol (alcohol is toxic to liver so it cannot break down glycogen to restore glucose)
How to does the anterior pituitary gland receive blood?
It has no arterial blood supply
Receives blood through portal venous circulation from the hypothalamus
What are ‘common’ diseases of the pituitary?
Benign pituitary adenoma
Craniopharyngioma
Trauma
Apoplexy/Sheehans
Sarcoid/TB
What are the 3 important presentations of pituitary tumour?
Pressure on local structures (eg. Optic nerves -> Bitemporal hemianopia)
Pressure on normal pituitary (hypo-pituitary)
Functioning tumour? (Ie does it produce hormones- prolactinoma, acromegaly, Cushing’s disease)
How does hypopituitary present in males?
Pale, no body hair, central obesity
What are the presentation of prolactinomas and how can we treat them?
Possible in men but more common in women
Present with galactorrhoea and amenorrhoae and infertility
Causes loss of libido and maybe visual field defect
Dopamine agonists often shrink the tumours
What are the tanner stages?
Stages of puberty
In boys it measures pubic hair, testicular length and testicular volume (also colour of scrotum and growth of penis)
In girls it measure pubic hair, papilla and areola
What is thelarche?
Breast development
= first visible sign of puberty
What are the differences between prepubertal and adult uterus on ultrasound?
Prepubertal- tubular shape, endometrium single layer of cuboidal cells
Adult- pear shape, endometrium increased thickness
What is adrenarche?
Maturation process of adrenal gland where specialised subset of cells arise to form the (androgen producing) zona reticularis
What is precocious puberty?
= true early puberty
Most are females
Most is idiopathic early puberty
But in boys it is more risky and may be due to brain tumours
How do you treat precocious puberty?
GnRH super-agonist that is so powerful it ultimately stops pulsatility of GnRH secretion and therefore cutting off the axis
What are indications for investigation of late puberty in girls?
No breast development by 13 yrs
More than 5 years between breast development and menarche
Lack of pubic hair by 14 yrs
Absent menarche by 15-16yrs
What are indications for investigation of late puberty in boys?
Lack of testicular enlargement by 14yrs
Lack of pubic hair by 15yrs
More than 5 years to complete genital enlargement
What are important laboratory investigations for late/early puberty?
Complete red blood count
U&E, renal, LFT and coeliac
LH, FSH, Testosterone/ Oestradiol- though these levels will be low during early puberty and quiescent phase
Thyroid function, prolactin
DHEA-S, ACTH, Cortisol
Karyotyping (esp in all girls with short stature - could be turner’s)
What can bone x-rays tell us with regards to puberty?
Bone age= skeletal maturity does not mean chronological age
Delayed bone age can be seen in GH deficiency
Advanced bone age can be seen in precocious puberty
What are common functional causes of delayed puberty?
Chronic renal or gastrointestinal disease
CF
Anorexia/ extreme exercise
Stress
Drugs
Sickle cell/iron overload
Cushing’s
In terms of normal axes, what are primary/secondary/tertiary problems?
Primary= the target organ eg gonads
Secondary= eg pituitary
Tertiary= eg hypothalamus
What is kallman syndrome?
Hypogonadotrophic hypogonadism caused by X-linked autosomal recessive or dominant mutation
What is Turner syndrome?
1 in 2000 girls
45XO genetics
Causes hypergonadotrophic hypogonadism
Causes cardiovascular malformations, short stature, broad chest and small mandible (jaw)
What is Klinefelter syndrome?
47XXY
Affects males- 1 in 1000
Causes primary hypogonadism (and therefore hypergonadotrophism)
Causes tall stature, breast cancer risk, slightly reduced IQ
What are the actions of parathyroid hormone?
Decreased phosphate reabsorption
Increased Ca2+ reabsorption
Increased bone remodelling
What happens to PTH when there is a smal; change in serum calcium?
Small decrease in Ca2+ -> large increase in PTH
Small increase in Ca2+ -> large increase in PTH
What are the consequences/symptoms of hypocalcaemia?
Parasthesia (tingling and numbness)
Muscle spasm
Seizures
Basal ganglia calcification
Cataracts
ECG abnormalities (LONG QT)
What are 5 possible causes of hypoparathyroidism?
Syndromes (incl Di George, HDR etc)
Radiation
Surgery
Genetics
Autoimmune
What is pseudohypoparathyroidism?
Resistance to parathyroid hormone
What are the symptoms/consequences of hypercalcaemia?
Thirst, polyuria
Nausea, constipation
Confusion -> coma
Renal stones
SHORT QT on ECG
What are possible causes of hypercalcaemia?
In 90% of cases:
Malignancy
Primary hyperparathyroidism
Otherwise:
Sarcoidosis, thiazides, adrenal insufficiency etc
What are the consequences/symptoms of hyperparathyroidism?
BONES, STONES, GROANS and MOANS
Osteoporosis
Kidney stone
Confusion (psychic groans)
Abdominal moans = constipation and acute pancreatitis
What are the possible causes of primary hyperparathyroidism?
80% due to a single benign adenoma
15-20% due to four gland hyperplasia
Less than 0.5% due to malignancy
What is the pituitary- thyroid axis?
The hypothalamus releases TRH (thyrotropin releasing hormone)
Causes the pituitary to release TSH
Causes the thyroid to release T4 and T3
T4 and T3 inhibit the release of TRH from the hypothalamus
What is the pituitary- gonadal axis?
Hypothalamus release GnRH (gonadatropin releasing hormone)
The pituitary releases LH and FSH
The gonads release testosterone/oestrogen
Testosterone/oestrogen inhibit the release of both GnRH and LH&FSH
What is the HPA axis?
(Hypothalamal-pituitary-adrenal)
The hypothalamus releases CRH (corticotropin releasing hormone)
The pituitary releases ACTH
Adrenals release cortisol
Cortisol inhibits the release of CRH and ACTH
What is the GH/IGF-1 axis?
(Growth hormone, insulin like growth factor-1)
The hypothalamus releases GHRH (growth hormone releasing hormone)
The pituitary releases GH
The liver releases IGF-1
IGF-1 inhibits the release of GRHR
Hypothalamus also releases Somatostatin which acts in an opposite way to GRHR!
What us the prolactin secretion axis?
The hypothalamus releases dopamine
The pituitary releases LESS prolactin
Prolactin encourages release of dopamine
What are the differences between pre-pubertal and adult external vagina?
Prepubertal is red in colour, thin strophic columnar epithelium with a neutral pH
Adult is duller red with thicker epithelium, superficial layers in epithelium and acidic pH. Labia increase in size and thickness, the hymen thickens and the clitoris enlarges
What histories must be taken when investigating delayed puberty?
Has it never started or did it start then stop?
Family history
Prenatal history
Prior illnesses/meds
Nutrition/exercise
Injury (testicular)
What is hypogonadotrophic hypogonadism?
When the lack of sex hormones produced is DUE to the lack of gonadotrophins
What is hypergonadotropic hypogonadism?
When gonads aren’t responding and aren’t producing sex hormones HENCE the Gonadotrophins are released in excess to try to get sex hormones to release
= primary gonadal failure
What are hormone replacement therapies for females?
Oestrogen by tablet or transdermal
Start with low dose and gradually increase
Once a full dose is achieved, add progesterone
What are hormone replacement therapies for males?
Testosterone enanthate = IM injection
Several incremental steps for 2-4 years until full adult replacement dose is achieved
What happens to PTH, calcium and phosphate in vitamin D deficiency and are the PTH levels appropriate?
In vit D deficiency:
PTH is up
Calcium is down
Phosphate is down
PTH levels are appropriate
What happens to PTH, calcium and phosphate in hypoparathyroidism and are the PTH levels appropriate?
In hypoparathyroidism:
PTH is down
Calcium is down
Phosphate is up
PTH levels are inappropriate
What happens to PTH, calcium and phosphate in pseudohypoparathyroidism and are the PTH levels appropriate?
In pseudohypoparathyroidism:
PTH is up
Calcium is down
Phosphate is up
PTH levels are appropriate
What happens to PTH, calcium and phosphate in hypercalcaemia of malignancy and are the PTH levels appropriate?
In hypercalcaemia of malignancy:
PTH is down
Calcium is up
Phosphate is ?
PTH levels are appropriate
What happens to PTH, calcium and phosphate in primary hyperparathyroidism and are the PTH levels appropriate?
In primary hyperparathyroidism:
PTH is up
Calcium is up
Phosphate is down
PTH levels are inappropriate
What are the presenting features of type 1 diabetes and why do they occur?
Thirst (osmotic activation of hypothalamus)
Polyuria
Weight loss and fatigue (loss of muscle and lipid due to unrestrained gluconeogenesis)
Hunger (lack of useable energy source)
Pruritis vulvae (itchy vulva) and Balanitis (red sore head of penis)
Blurred vision (altered acuity due to uptake of glucose)
What are the genetics behind type 1 diabetes (as in within families)?
Risk if mother has it: 2%
Risk if father has it: 8% (and symptoms are worse)
Risk if both parents have it: 30%
Risk if sibling has it: 10%
(15% if twin, 40% if identical twin)
What are the types of autoimmune diabetes type 1?
Anti- GAD
Pancreatic islet cells Ab
Islet antigen-2 Ab
ZnT8
Also associated with other autoimmune diseases incl hypothyroidism, addisons and coeliac
Why does ketoacidosis occur in type 1 diabetics?
Reduced insulin leads to fat breakdown to form glycerol + FREE FATTY ACIDS (FFA)
FFA are transported to the liver to provide energy for gluconeogenesis
FFA are oxidised to form ketone bodies
What is the definition of ketoacidosis?
Hyperglycaemia
Raised plasma ketones
Metabolic acidosis
What are the clinical features of diabetic ketoacidosis?
Symptoms develop over days, incl: polyuria, nausea, vomiting, weight loss, weakness, abdominal pain, drowsiness/confusion
Signs also are hyperventilation, dehydration, hypotension, tachycardia and comas
What biochemical signs make a diagnosis of diabetic ketoacidosis?
Hyperglycaemia = <50mmol/l glucose
Acidosis = <15 mol/l HCO3-
Urinary ketone dipstick of 2+ ketones/ blood ketones of 3 ketones
How do you treat/manage diabetic ketoacidosis?
Insulin
Rehydration
Replacement of electrolytes
Start immediately!
What are the microvascular complications of diabetes type 1?
Diabetic nephropathy (kidney disease)
Retinopathy
What are the consequences of too much insulin/ hypoglycaemia?
Acute deprivation of glucose within the brain -> cerebral dysfunction
Release of glucagon and adrenaline
Sweating, tremor, palpitations, loss of concentration and hunger
What is DAFNE in diabetes?
Dose Adjusting For Normal Eating
What is MODY?
Maturity-onset diabetes of the young
What are the features of MODY?
Commonest monogenic diabetes
Diagnosed younger than 25
Autosomal dominant
Single gene defect altering beta cell function
What are the different types/causes of MODY?
Transcription factor MODY (where hepatic nuclear factor HNF alters insulin secretion and reduces beta cell proliferation)
MODY 3 = HNF1A mutation
MODY 1 = HNF4A mutation (neonatal hypoglycaemia)
MODY 2 = GCK mutation (GCK is the glucose sensor or beta cells- causes mild diabetes)
What factors help determine a diagnosis of MODY?
Parent with diabetes
Absence of islet antibodies
Evidence of non-insulin dependence
No ketosis and measurable to C-peptide
Sensitive to sulphonylurea (especially MODY 3)
What is C-protein (in the context of diabetes)?
Insulin is released as Pro-peptide (insulin + c-peptide)
Very measurable in blood
Significant levels= they’re making their own insulin
What is MIDD (diabetes) and how does it occur?
Maternally inherited diabetes and deafness
Caused by mutation to mitochondrial DNA & loss of beta cell mass
What is lipodystrophy?
Selective loss of adipose tissue
Associated with insulin resistance, hyperandrogenism and PCOS
What are the consequences of pancreatitis?
Acute pancreatitis -> short lasting hyperglycaemia due to glucagon secretion
Chronic pancreatitis alters secretion and causes blocked ducts, must be treated with insulin
What are the features of hereditary hemochromatosis?
It is autosomal recessive causing a traid of cirrhosis, diabetes and bronzed hyperpigmentation
Excess iron is deposited in the liver, pancreas, pituitary, heart and parathyroids
Most people with it need insulin
How does cystic fibrosis cause diabetes?
The viscous secretions caused by CF lead to duct obstruction and pancreatic fibrosis
What is a GOITRE?
Enlargement of the thyroid causing swelling in the neck
Can be benign or malignant
What are the 3 mechanisms for increased levels in hyperthyroidism?
Overproduction
Leakage
Ingestion of excess hormone
What are the clinical features of hyperthyroidism?
Weight loss
Tachycardia
Anxiety
High temperature/sweating
Diarrhoea
What are the 3 most common causes of hyperthyroidism?
Graves’ disease (up to 80% of all cases) -> diffused goitre
Toxic multinodular goitre
Toxic adenoma
What are specific signs of Graves’ disease?
Diffuse goitre
Thyroid eye disease
Acropachy (looks exactly the same as clubbed fingers)
Pretibial myxoedema (swelling and red rash of lower leg)
What is a specific sign of toxic adenomas?
Solitary nodule
What would you see in investigations of primary hyperthyroidism?
Increased free T4 and T3
Suppressed TSH
What would you see in investigations of secondary hyperthyroidism?
Increased T4 and T3 (DUE TO)
Inappropriately high TSH
What are treatment options for hyperthyroidism?
Anti thyroid drugs (sometimes partial, sometimes complete and then replace hormones with thyroid meds)
Radioiodine (iodine targets thyroid cells so using radioactive targets these cells)
Surgery
What are common examples of anti-thyroid drugs?
Thionamides
Carbimazole
Propylthiouracil (good for women who are pregnant/ wanting to get pregnant)
What is the most important possible side effect of thionamides (anti-herperythyroids)?
Agranulocytosis (-> neutropenia = very low white blood cell count)
What are the clinical features of HYPOthyroidism?
Fatigue
Weight gain
Too cold
Constipation
Slow cerebral ion
What are the common causes of hypothyroidism?
Hashimoto’s thyroiditis (autoimmune)
Radioiodine therapy
Thyroidectomy
Hormone resistance
Pituitary an hypothalamic disease
What would be seen in clinical investigation of primary hypothyroidism?
High TSH
Low free T4 and T3
What would be seen in clinical investigation of secondary hypothyroidism?
Inappropriately low TSH considering how low T4 and T3 are
What are treatments for hypothyroidism?
Synthesis levothyroxine (synthetic T4) of a weight based dose (1.6microg per kilo)
Also synthetic T3 but on NHS they use T4
What is Grave’s disease?
Autoimmune where body attacks/makes antibodies for the tyroid
Causes HYPERthyroidism
What antibodies are almost always found in autoimmune hypothyroidism?
Thyroglobulin
Thyroid peroxidase (TPO)
What are the antibodies responsible for Grave’s disease?
Once called ‘long acting thyroid stimulators’
Now called thyroid stimulating antibodies
They are TSH-receptor antibodies
What are risk factors for thyroid autoimmunity?
Genetic and environmental
Being female
Immunoregulatory genes eg HLA-DR3
Stress, iodine intake, smoking
What are the autoimmune diseases associated with thyroid autoimmunity?
Type 1 diabetes
Addison’s
Pernicious (harmful) anaemia
Vitiligo
Slope is
Coeliac
Hepatitis
RA
Grave’s
What is thyroid associated opthalmopathy?
Swelling of the extraocular muscles
(Present in most Grave’s patients)
Where are the posterior pituitary hormones made and transported?
Vasopressin and oxytocin are made in the paraventricular nucleus and supraoptic nucleus
They are transported to the posterior pituitary in the axoplasm of the neurons
What are the receptors that vasopressin/ADH binds to and what does each do?
V1a= binding causes vasoconstriction and therefore increased BP
V2= causes reabsorption of water in the renal collecting tubules
V1b= binds to the anterior pituitary to cause release of ACTH
How do intra and extracellular fluid differ in their ionic composition?
Extracellular has much more Na+ than intra
Intracellular has much more K+ than extra
Extra has a little Ca2+, intra has a little (more) Mg2+
Extracellular has much more Cl- than intra
Intracellular has much more phosphate and organic anions than extra
Extracellular has some HCO3-, more than intra
Intracellular has some protein, more than extra
What does increased vasopressin release to do urine output?
Makes LESS urine
So more reabsorption of water by kidneys
What is the mechanism of action of vasopressin in the kidneys?
Vasopressin activates V2 receptors in collecting ducts
Aquaporin-2 proteins are synthesised and inserted into the apical membrane
Permeability of CD is increased
Water is reabsorbed and returned to the blood
What is osmolality, and what are substances that affect it?
Concentration of substances in blood/plasma per kilo
(Size of particle is not important but number is!)
Sodium, potassium, chloride, bicarbonate, urea and glucos are present at high enough concentrations to affect osmolality
What is the affect of ADH on urine osmolality?
The more plasma ADH, the greater the osmolality of urine (ie. The less water, so the more substances per kilo)
What are the 3 main diseases associated with the posterior pituitary?
Lack of vasopressin= ADH deficiency (cranial diabetes insipidus) = uncommon but life threatening
Resistance to action of ADH= ADH resistance (nephrogenic diabetes insipidus) = uncommon but life threatening
Too much vasopressin (when it should not be released)= SAID (syndrome of anti-diuretic hormone secretion)= really common but can be life threatening, causes can be ectopic carcinomas
What are the features of Diabetes insipidus?
= ADH deficiency and resistance
Polyuria
Polydipsia
No glycosuria
Inappropriately dilute urine for plasma osmolality
What are causes of ADH deficiency (cranial diabetes insipidus)
Acquired causes include tumours, trauma, infection (incl TB, encephalitis, meningitis), inflammation (guillian barre and granuloma), vascular (incl aneurysm, infarction and sickle cell) and idiopathic
Primary causes include genetics and developmental disease
What are the features of nephrogenic diabetes insipidus?
= ADH resistance
Familial nephrogenic DI is rare but can occur (X-inked or autosomal)
Acquired causes incl osmotic diuresis (eg diabetes mellitus), drugs, renal impairment etc
What is a water deprivation test?
Tests for release of ADH and therefore change in urine osmolality under water deprivation.
What would you expect to see in a water deprivation test for a normal response, an ADH deficiency and an ADH resistance response?
A normal response should show an increase in ADH causing an increase in urine osmolality over hours, with a large increase after ~13hrs.
An ADH deficiency response would show no increase in urine osmolality until 16hrs.
An ADH resistance response would show a very slow, steady and small increase in urine osmolality.
What is copeptin and why do we measure it?
Copeptin is released at a 1:1 ratio with ADH
It is measured to see levels of ADH because ADH levels are hard to measure- it has a short half life but copeptin doesn’t and it therefore is measurable
How is cranial diabetes insipidus managed?
= ADH deficiency
Any underlying conditions/causes should be treated
Give desmopressin= high acuity at V2 receptors
(Tablets of 100-600 mg/day
Nasal spray of 10-20 mg/day
Injection of 1-2 mg/day)
What are 5 examples of pituitary mass lesions?
Non-functioning pituitary adenomas
Endocrine active pituitary adenomas
Malignant pituitary tumours (functional and non-functional carcinomas)
Metastasis in the pituitary (from breast, lung, stomach and kidney)
Pituitary cysts
What are craniopharyngiomas?
Pituitary cysts (can be arising in the squamous epithelial remnants of Rathke’s pouch)
These are benign but often infiltrate surrounding structures
What are Rathke’s cysts?
Cysts on the pituitary that arise from remnants of Rathke’s pouch
Mostly asymptomatic and small
May present with headaches, amenorrhoea, hypopituitarism and hydrocephalus
What are meningiomas?
Common tumours of regions after pituitary adenoma as a complication of radiotherapy
Can cause visual and endocrine disturbance
What is lymphocytic hypophysitis?
Inflammation of the pituitary gland due to an autoimmune reaction (occurs often in women at the end of/after pregnancy- 6:1 more common in women)
What are non-functioning pituitary adenomas?
Tumours on the pituitary that are not producing any hormones
Often found incidentally
Often only found when they grow to a point where they are causing other organs to misfunction = tumour mass effects
What are 3 signs that should cause you to investigate pituitary tumours?
Tumour mass effects (eg. Visual field defects, headaches)
Hormone excess
Hormone deficiency
What are common tumour mass effects of pituitary tumours?
Cranial nerve palsy/epilepsy
Headaches
Visual field defects
CSF rhinorrhoea (leaking through the nose)
What is the preferred imagine for study of the pituitary?
MRI
How do you treat adrenal insufficiency?
Hydrocortisone
(Immediate release hydrocortisone gives a big peak when first taken and goes down so patients are given tablets one after the other every 6 hours with doses getting smaller to mirror the natural levels of cortisol reducing through the day)
(Modified release HC has slower release)
How do you treat thyroxine insufficiency?
Daily tablet
1.6mg/kg/day
Start low and increase to mid/upper of reference range
How is growth hormone insufficiency treated?
Daily IGF-1
0.2-0.4mg/day for <60yrs
0.1-0.2mg/day for >60yrs
How do we treat ADH insufficiency?
Desmopressin
Works immediately- patients see change within days
Sub-lingual, oral or sub-cutaneous
How do you treat gonadal hormone insufficiency?
Testosterone replacement with gels/orals/injections
Oestrogen replacements with oral oestrogen or oestrogen and progesterone
What is the most common cause of hyponatramia?
Excess water
( ie not insufficient salt)
What is a serum sodium level indicative of hyponatraemia?
<135 mmol/l
What are symptoms of hyponatraemia?
Moderate symptoms include headache, irritability, nausea/vomiting, mental slowing, falls, confusion and disorientation
Severe symptoms include comas, convulsions and respiratory arrest
What are the biomechanical classifications of hyponatraemia?
Mild: 130-135mmol/l
Moderate: 125-129mmol/l
Severe: <125mmol/l
What are the aetiologic classifications of hyponatraemia? (Ie fluid volume)
Hypovolaemic (low fluid volume)
Euvolaemic (normal/level fluid volume)
Hypervolaemic (high fluid volume)
What is SIAD?
Syndrome of inappropriate antidiuresis
(Causes 25% of all hyponatraemia)
Causes too much ADH
What are CNS causes of SIAD?
= syndrome of inappropriate antidiuresis
Head injury
Meningitis
Encephalitis
Brain tumour/abscess
Haemorrhage
Guillian barre
What are respiratory cases of SIAD?
= syndrome of inappropriate antidiuresis
Pneumonia
TB
Severe asthma
Emphysema
How is SIAD managed?
= syndrome of inappropriate antidiuresis
Diagnose and trust underlying conditions
Restrict fluid
If Na is low, give saline on ITU
What are risk factors for osmotic demyelination syndrome?
Very low serum Na+
Hypokalaemia
Chronic excess alcohol
Malnutrition
Liver disease
What is tolvaptan?
Competitive antagonist to ADH
Licensed to treat SIAD
What is diabetic neuropathy?
Damage to nerves caused by diabetes
What are the symptoms of diabetic neuropathy?
Causes “glove and stocking” sensory loss
Burning
Parasthesia (burning/prickling in periphery)
Foot ulceration
Erectile dysfunction
Diarrhoea/constipation/incontinence
Falls
What is the difference between acromegaly in adults vs children?
In children the over-growth is allowed because bony epiphyses have not yet fused
This causes gigantism in children
In adults the bony epiphyses have fused so growth is not allowed in the same way
What are the 7 main comorbidities of acromegaly?
Hypertension
Headaches
Sleep apnea
Insulin-resistant diabetes
Arthritis
Dental problems due to the overgrowth of the jaw
Visual field defects if due to pituitary tumour
What are the 6 main presenting features of acromegaly?
Acral enlargement (hands and feet)
Arthralgias ( joint pain )
Maxillofacial changes (face/jaw)
Hypogonadism symptoms
Excessive sweating
Headaches
How can you use GH levels to diagnose acromegaly?
GH is pulsatile and in normal people levels return to almost 0 inbetween pulses
GH in acromegaly has many more pulses but will never return to the normal low level inbetween pulses
Therefore one large GH measure CANNOT diagnose acromegaly but one very small measure of GH CAN rule out acromegaly
What are treatment options for acromegaly?
Pituitary surgery
Radiotherapy (incl conventional, steriotactic, LINAC, proton beam or gamma knife!)
Dopamine agonists can control GH and therefore IGF-1
Somatostatin analogues
PEGVISOMANT= GH competitive agonist which prevents GH clearance
What are the symptoms of prolactinoma?
Headache
Visual field defect
(Rare) CSF leak
Amenorrhoea
Low libido
Infertility
Hypogonadism (prolactin-mediated supression of gonadotrophins)
What is the best option for removal/treatment of pituitary tumours?
Trans-sphenoidal surgery
How are prolactinomas managed?
Medically rather than surgically
Dopamine agonists (mainly cabergoline)
Shrinks tumours immediately
What is intermittent claudication?
Cramping in the calf/thigh muscle while walking / not at rest
What are signs of vascular disease in diabetes?
Diminished or absent pedal (foot) pulses
Coolness of the feet and toes
Poor skin and nails
Absence of hair on feet and legs
Why is it always important to check the feet of those with diabetes, and what do you check for?
To ensure there is no neuropathy or vascular disease
Must check for circulation and ulcers, skin cracking and ability to feet pain
What are risk factors for diabetic retinopathy?
Long duration diabetes
Poor glycaemic control
Pregnancy
People on insulin treatment (due to the ischaemic region or the retina)
What is the eye screening programme for diabetics?
Once-yearly screening for diabetic retinopathy
Takes photographs of the retinas which are graded
What is the pathogenesis of diabetic retinopathy?
Leaking and Occlusion
Leakage= basement membrane thickens and pericytes are lost so junctional contact with endothelial cells is reduced
Occlusion= combo of cells being lost/thickening leads to ischaemia/ glial cells grow down the capillaries = occlusion
Lead to retinal hypoxia
How is diabetic retinopathy managed?
Cannot be reversed, can be managed by laser treatments where abnormal blood vessels are burned
What is the hallmark for development of diabetic nephropathy?
Proteinuria
What is the pathophysiology of diabetic nephropathy?
Thickening of glomerulas
Increase glomerular and systematic pressure
Increased injury of glomerulus
Filtration of proteins/ other molecules that shouldn’t be
How is diabetic kidney disease classified?
Into 5 grades based on glomerular filtration rate
Grade 1 being 90-105 ml/min/1.73m^2
Grade 5 being <15 or someone on dialysis
How is diabetic nephropathy managed?
BP control
Glycemic control
Reduce proteins to prevent proteinuria
What is Addison’s?
Adrenal insufficiency (hypocortisolism)
What is the HPA axis?
Hypothalamus releases corticotropin releasing hormone
Pituitary releases ACTH
Adrenals release cortisol
Cortisol inhibits release of both ACTH and CRH
What is the cortisol circadian rhythm?
Low at night
Builds up from 3am until it peaks at 8/9am ish- whenever you wake up
Falls throughout the day
What is the suprachiasmatic nuclei?
A nucleus within the anterior hypothalamus which has a role in regulating the circadian rhythms of different hormones
Adrenal insufficiency = cortisol ??????
Deficiency
What are the common cause of Addison’s disease?
Autoimmune
TB
What is the most common cause of adrenal insufficiency?
Steroids
What are the symptoms of adrenal insufficiency?
Fatigue
Weight LOSS
Poor recovery from illness
What are the clinical presentations of adrenal insufficiency?
Symptoms: fatigue, weight loss, poor recovery from illness
History: TB, post partum haemorrhage, cancer and treatment with steroids
Family history of autoimmune
Pigmentation (as ACTH acts on melanin receptors)
Pallor (pale)
Biochemical signs (low Na, high K, eosinophilia and borderline high TSH)
Explain the biochemical signs of adrenal insufficiency?
Low Na and High K = due to cortisol is important in excretion of water load AND aldosterone from adrenal glands
Eosinophilia (high levels of eosinophils)
Borderline elevated TSH (in primary adrenal insufficiency)
How do you investigate adrenal insufficiency?
Ideally would measure CORTISOL first thing in the morning- when it should be at its highest
Do a stimulation test where inject synthetic ACTH
You can measure CORTISONE (a derivative of cortisol) in SALIVA- ask people to spit as soon as they wake up
What is adrenal crisis?
When adrenal glands make so little cortisol and someone has an illness causing the body goes into crisis
How is adrenal crisis treated?
Immediate hydrocortisone (100mg IV or IM)
Continue 50-100mg hydrocortisone every 6 hours
(Hydrocortisone is cortisol)
Wean dose down to replacement dose or else you will cause cushing’s (Excess steroid)
Sick day rules!?
What are sick day rules in context of adrenal crisis?
Have to double your dose of steroids if you are unwell (if in doubt- double dose)
If vomiting/ getting more ill have emergency injection of 100mg hydrocortisone IM!!!!!
Short term excess steroid is not damaging
How is adrenal insufficiency treated?
Glucocorticoid replacement with daily hydrocortisone (first thing 10mg, 5mg at lunch and dinner)
Mineralocorticoid replacement if primary
Androgen replacement
How have drug companies created cortisol drugs which closely mimic the circadian rhythm?
They have created a drug (chronocort = efmody) which has an outer layer that cannot allow the drug polymer to escape until it reaches the small bowel
= allows slow release over night as opposed to high peaks immediately after taking the drug
What are the 3 main risk factors for angina?
Family history
Smoking
Age
What are the 3 categories of exacerbating factors for angina- give examples of each?
Those that affect supply (anemia, Hypoxemia)
Those that affect demand (hypertension, tachyarrythmia)
Environmental (stress, exercise, cold weather)
What are 3 clinical risk factors for coronary heart disease?
Hypertension
Hyperlipidemia
Diabetes
What are 3 lifestyle risk factors for coronary heart disease?
Smoking
Diet
Physical inactivity
What is an environmental risk factor for coronary heart disease?
Air pollution
What are 3 demographical risk factors for coronary heart disease?
Age
Sex
Ethnicity
What are the layers of the pericardium?
Two layers:
Visceral single cell (connected to epicardium)
Fibrous parietal with attachments that fix the heart in the thorax
What are the possible causes of pericarditis?
Commonly viral (enteroviruses, herpesvirus etc)
Bacterial causes incl mycobacterium TB
Non-infectious causes incl autoimmune (RA, sjorgren), neoplastic (secondary to lung/breast), metabolic or from trauma
What are the clinical presentations of pericarditis ?
Chest pain which is severe, sharp with rapid onset and relieved by sitting forward
Other symptoms that would indicate viral/bacterial infection in some cases
What are the features of an ECG that would diagnose pericarditis?
Widespread ST saddle shaped
J point elevation
PR depression (in leads I, II, III, aVL, aVF and V2-6)
What is cardiac tamponade?
The pressure on the heart when there is a build up of fluid in the pericardial space
(Small amounts of fluid removed or added make a large difference)
Why are cardiac tamponades rarely caused by chronic effusion?
Because when effusion is chronic the parietal pericardium has time to slowly stretch and build up compliance
How is pericarditis managed?
Reducing exercise until symptoms resolve
NSAIDs in large doses
What is the pericardial rub?
A sound produced during pericarditis
What is atherosclerosis?
Build up of substances incl fats and cholesterol on vessel walls
Why is atherosclerosis so dangerous?
If atherosclerotic plaques rupture they can cause partial of complete arterial blockage -> heart attacks, stroke of gangrene (tissue death)
What are 8 risk factors for atherosclerosis?
Age
Smoking
High serum cholesterol
Obesity
Diabetes
Hypertension
Family history
What is the structure of an atherosclerotic plaque?
Complex lesion consisting of lipid, necrotic core, connective tissue and fibrous ‘cap’
What is the ‘response to injury’ theory of atherosclerosis?
The theory that atherosclerosis is initiated by an injury to endothelial cells which leads to endothelial dysfunction- signals are then sent to cause circulating leukocytes to accumulate and migrate into the vessel wall -> inflammation (LDLs accumulate in excess witching the arterial wall and undergo oxidation and glycation)
What is the relevance of LDLs in atherosclerosis?
LDLs accumulate in excess witching the arterial wall and undergo oxidation and glycation
What is the stimulus for adhesion of leukocytes in atherosclerosis?
After initiation of inflammation, chemoattractants (for leukocytes) are released from the site of injury (causing conc grad)
What are the inflammatory cytokines found in plaques?
IL-1
IL-6
IL-8
(TGF B (transforming growth factor beta), Interferons and MCP-1 (monocyte chemoattractant protein -1 which induces IL release) are also present)
What is a ‘fatty streak’ in atherosclerosis?
The earliest lesion of atherosclerosis
Consist of lipids macrophages and T lymphocytes within the intima
What are intermediate lesions of atherosclerosis?
The second lesion of atherosclerosis
Consists of layers of foam cells (macrophages -> foam cells when they insult LDLs), smooth muscle cells and T lymphocytes
Also platelets adhered to vessel wall
What are fibrous plaques/ advances lesions of atherosclerosis?
3rd stage of atherosclerotic lesion
Blood flow is impeded
These are prone to rupture
Plaques are converted by the fibrous cap (made of collagen and elastin)
Lesion contains SMCs, lipid core and necrotic debris, FOAM cells and T lymphocytes
What happen during atherosclerotic plaque rupture?
Plaques rupture when the cap becomes weak
This may be due to shit in balance of inflammatory conditions
What is atherosclerotic plaque rupture vs erosion?
Plaque erosion is in plaques with no/a small lipid core and with more fibrous tissue.
Plaque rupture is of plaques rich in inflammatory cells.
How are plaque ruptures and plaque erosions treated differently?
Erosions: anti-thrombotic
Ruptures= stents
What are the differences in outcomes of plaque erosions vs ruptures?
In erosions there is less microvascular damage and better myocardial perfusion
In ruptures there is no re-flow after intervention and higher risk of major cardiac event
What are the differences in clinical characteristics of atherosclerotic plaque rupture vs erosion?
In erosions there is less microvascular damage and better myocardial perfusion
In ruptures there is no re-flow after intervention and higher risk of major cardiac event
What are the differences in clinical characteristics of atherosclerotic plaque rupture vs erosion?
Erosions are more common in younger women, smokers and in the summer. Often occur near a bifurcation
Plaques occur more with hypertension, diabetes, kidney disease and during the winter
What is PCI?
Percutaneous coronary intervention
= family of non-invasive procedures that open coronary arteries
Why is aspirin relevant to atherosclerosis?
It is an irreversible inhibitor of the platelet cycle-oxygenate so helps to reduce risk of cardiac events due to atherosclerosis
What do statins do?
Reduce cholesterol synthesis (by inhibiting HMG CoA reductase)
What do PCSK9 inhibitors do?
Improve clearance of cholesterol from the blood by inhibiting PCSK9 protein in the liver
What are the 4 major cell types involved in atherogenesis?
Endothelium
Macrophages
Smooth muscle cells
Platelets
What does the term ‘acute coronary syndromes’ cover?
Spectrum of acute cardiac conditions from unstable angina to varying degrees of evolving myocardial infarction
What would be seen in an ECG with Q wave infarction?
ST elevation
What would be seen in an ECG with non-Q wave infarction?
ST depression / T wave inversion
What would be seen in an ECG of unstable angina?
No changes!
What is unstable angina?
Cardiac chest pain at rest and new onset
Which is worse, Q wave infarction or non-Q wave infarction?
Q wave = ST elevation
as usually associated with larger infarcts
What is the significance of ST elevation in diagnosis of MI?
ST elevation means MI diagnosis usually
Non-ST elevation means there is a retrospective diagnosis of MI maybe due to troponin results or other investigation
What is the J point of an ECG?
The point after the QRS complex where you can see if there is ST elevation/depression or not
How are myocardial infarctions initially managed?
PCI if ST elevation
300mg aspirin immediately
Pain management
What is the importance of troponin in MI?
Troponin is a marker for cardiac muscle injury (but no specific to acute coronary syndrome)
What is tetralogy of fallot?
A combination of 4 congenital heart defects:
Ventricular septal defect
Pulmonary stenosis
Hypertrophy of right ventricle
Overriding aorta
What occurs in tetralogy of fallot?
Right ventricle hypertrophy and septal defect means unoxygenated blood from right ventricle passes into the left ventricle
What are 5 common structural heart defects?
Ventricular septal defect
Atrial septal defect
Atrio-ventricular septal defects
Patent ductus arteriosus
Coarctaction of aorta
What occurs in ventricular septal defects?
Abnormal connection between RV and LV (‘hole’ in septum)
Blood flows from high pressure LV into low pressure RV
What are the clinical signs of large ventricular septal defects?
Small skinny baby
Breathless
Tachycardia
Increased resp rate
Large heart
Murmur
What is eisenmenger’s syndrome?
A complication of non-treated ventricular septal defect
Causes high pressure pulmonary blood flow and hence damage to pulmonary vasculature as well as high RV pressure and BLUE patient
What are atrial septal defects?
Abnormal connections between atria (pressure in LA is slightly higher than RA so blood shunts into RA)
What are the clinical signs of atrial septal defects?
Pulmonary flow murmur
Delayed closure of pulmonary valve
Big pulmonary arteries
Big heart
What is atrio-ventricular septal defect and with what condition does it often occur?
Basically a hole in the very centre of heart
Often with Down syndrome
Involves A septum and V septum and mitral and tricuspid valves
What are the types of atrio-ventricular septal defects?
Types describe the way in which blood is shunted due to the position/shape of any septum:
Interatrial
Interatrial and interventricular
Interventricular
What is a patent ductus ateriosus?
The presence of the ductus arteriosus (meant to disappear in birth)= more common in prem babies
DA is a shunt in neonates between aorta and pulmonary vein
What is coarctation of the aorta?
Narrowing of the aorta at the site of insertion of the ductus arteriosus
What is the physiology of severe coarctation of the aorta?
Complete or almost obstruction of aortic flow
Needs urgent repair
(Murmur)
How is coarctation of the aorta treated?
Surgical or percutaneous (through skin)
Either with end to end repair or with a subclavian flap
What is bicuspid AV?
A normal AV valve has 3 cusps, in bicuspid there are 2, they degenerate and becomes regurgitate earlier than normal valves
What is pulmonary stenosis?
Narrowing of pulmonary valves and of the right ventricle
What happens in severe pulmonary stenosis?
Right ventricular failure
Poor pulmonary blood flow
RV hypertrophy
Valve regurgitation
How is pulmonary stenosis treated?
With balloon valvuloplasty/ open valvotomy/ shunt
What are the 3 main risk factors for angina?
Age
Smoking
Family history
What are the 3 categories of exacerbating factors for angina- give 2 examples for each?
Those that affect supply of oxygen to the heart (anemia, hypoxemia)
Those that affect demand of oxygen (hypertension, tachyarrhythmia)
Environmental factors (exercise, stress, cold weather)
What are the 3 types of angina?
Crescendo angina (gets worse and worse)
Unstable angina= pain at rest- bad
Microvascular angina= angina when the normal coronary arteries aren’t to blame
What do you have to remember when prescribing beta blockers?
ASTHMA! Cannot be given to people with asthma
What drugs may be given for angina?
Beta blockers (slow HR)
Nitrates (incl GTN spray)
Statins
Calcium channel blockers
ACE inhibitors
Aspirin
What are coronary artery bypass grafts?
When new vessels are surgically placed to bypass ones that are not working properly- can either be with veins from leg or with internal mammary artery
What is a summary of heart embryology?
The heart comprises of a single chamber until the 5th week of gestation where it becomes divided by intra-atria and intra-ventricular septa
The inta-v septum grows upwards from the apex to produce the 4 chambers
Which congenital heart conditions produce a left-right shunt?
VSD, ASD, PDA
Which congenital heart conditions produce a right-left shunt?
Tetralogy of fallot, tricuspid atresia
What is endocardial fibroelastosis?
Stiffening of the heart either primary or secondary to aortic stenosis and coarctation.
What is dextrocardia?
Normal anatomy of the heart but with rightward orientation- often associated with other organ isomerism
What is reperfusion of ischaemic myocardium?
Reperfusion of tissue following ischaemia once allowed by clot-busters or angioplasty.
What are the risks involved with reperfusion of ischaemic myocardium?
Reperfusion of completely infarcted tissue can produce significant haemorrhage and more injury
What is an aneurysm?
A dilation of part of the myocardial wall (usually associated with fibrosis and atrophy of myocytes).\dilation of thin walled sac allows blood stasis and thrombosis
What is dressler syndrome?
Pericarditis
What is hypertensive heart disease?
Cardiac enlargement due to hypertension and no other cause
What are the histological features of hypertensive heart disease?
Initially increased myocyte size, squaring of the nuclei and a slight increase of the interstitial fibrous tissue
What is cor pulmonale?
Right ventricular hypertrophy/dilation due to pulmonary hypertension (disproportionate to the left). Progressive features incl right sided heart failure and oedema
What is infective endocarditis?
Infective process involving cardiac valves causing valve distortion and disruption with cardiac function
How does aspirin help stop clots from forming?
Blocks platelet release of thromboxane A2 (a chemical which promotes the positive feedback loop for coagulation)
What type of drugs are P2Y12 inhibitors?
Anti-platelets
What type of drugs are Glycoprotein IIb/IIa antagonists?
Anti-platelets (used in higher risk settings)
What is the most common anti-coagulant?
Heparin or low-molecular weight heparin
Give an overview of how acute coronary syndromes are managed?
Pain relief if necessary
Aspirin and p2Y12 inhibitors for anti-platelets
Anticoagulants
Anti-angina therapy (incl beta blockers etc)
Secondary prevention
What is the first course of treatment for a STEMI?
PCI (stent)
What is the first course of treatment for an NSTEMI
Similar with unstable angina- most commonly PCI in a less time-critical way
Sometimes coronary bypass graft
What is infective endocarditis
Infective process involving cardiac valves causing valve distortion and disruption with cardiac function
What myocarditis?
Inflammation of the myocardium usually associated with muscle cell necrosis and degeneration.
Most commonly viral.
What is hypertrophic cardiomyopathy?
Unexplained primary cardiac hypertrophy- genetic affecting 1/500 people
What causes the symptoms of hypertrophic cardiomyopathy?
Hearts are stiffer and less elastic so are harder to fill in diastole. This is due to disorganisation of myocytes.
What is dilated cardiomyopathy?
Thin cardiac walls caused by cytoskeletal gene mutations. Causes heart failure.
What is arrhythmogenic cardiomyopathy?
Programmed replacement of cardiac myocytes with fibrous/fatty cells caused by desmosome gene mutations
What is restrictive cardiomyopathy?
A group of diseases where heart has more dilation- has classic low voltage ECG.
What are 4 examples of chanelopathies?
Long QT
Short QT
Brugada
CPVT
What must you remember with long QT syndrome?
A lot of drugs prolong QT and therefore can kill people already suffering with long QT!
What are cardiac myxomas?
The cause of 75% of cardiac tumours
Normally in the atria
What is rhabdomyoma?
Paediatric cardiac tumour
What are common diseases of the pericardium?
Pericardial effusion
Haemopericardium (direct bleeding from vessels through ventricle wall following MI)
Cardiac tamponade
Pericarditis
What is the min theory of clot lysis?
Conversion of plasminogen into plasmin which acts on fibrin to produce fibrin degradation products
What is a berry aneurysm?
A vascular dilation in the cerebral circulation (in the circle of willis)
What is a dissecting aneurysm?
A tear in the aorta (mostly above the aortic ring)
What are varicose veins?
Enlarged torturous vein predominantly in the superficial leg veins
Causes progressive incompetence of valves with back pressure
What are the main vascular tumours?
Haemangioma
Glomus tumour
Haemangioendothelioma
Angiosarcoma
Kaposi’s sarcoma
What are the features of kaposi’s sarcoma?
It is linked to HIV and AIDS- human herpes virus 8
= purple/brown nodule often on the skin
What is familial hypercholesterolaemia?
Inherited abnormality of cholesterol metabolism or sometimes problems with LDL receptors.
Leads to serious premature coronary/vascular disease
What are the main antihypertensives?
ACE inhibitors
ARBs (angiotensin II receptor blockers)
Calcium channel blockers
Beta-adrenoreceptor blockers
Diuretics
What is aortic stenosis?
Narrowing of the aortic valves
What are the 3 main symptoms of aortic stenosis?
Syncope on exertion
Angina
Dyspnoea (shortness of breath) on exertion
What (if any) murmur can be heard in aortic stenosis?
An ejection murmur
Crescendo- decrescendo
What is a measure of how bad an aortic stenosis is?
AS is graded based on AVA (valve area)
How is aortic stenosis managed?
Rate control
Anticoagulants
Regular ECHOs
IE prophylaxis
What is mitral regurgitation?
Backflow of blood from LV to LA during systole
What are the 2 main physical signs of mitral regurgitation?
LA enlargement
LV hypertrophy
What (if any) murmur can be heard in mitral regurgitation?
A pansystolic murmur at the apex
What are the symptoms/pathophysiology of mitral regurgitation?
Exertion dyspnoea
Compensatory phase of 10-15 which causes mechanisms incl LA enlargement and LV hypertrophy
What is aortic regurgitation?
Leakage of blood into the LV during diastole
What are 3 possible causes of aortic regurgitation?
Bicuspid aortic valves
Rheumatic causes
Infective endocarditis
What (if any) murmur can be heart in aortic regurgitation?
Diastolic decrescendo murmur at the left sternal border/ systolic ejection murmur
What are the progressive symptoms that may be seen in aortic regurgitation?
Exertion dyspnoea moving to orthopnea (dyspnoea when lying down) moving do nocturnal dyspnoea
What may be seen in X-rays/ECHOs of aortic regurgitation?
Enlargement of the aortic root, enlarged cardiac silhouette
What is mitral stenosis?
Obstruction of the LV inflow that prevents proper LV filling during diastole
What are the most common causes of mitral stenosis?
99% caused by rheumatic carditis
Sometimes caused by infective endocarditis
What (if any) murmur can be heart in mitral stenosis
Diastolic low pitched murmur like a rumble which is most prominent at the apex
What is a common sign of mitral stenosis?
Mitral facies= pink/purple patches on the cheeks
What may X-rays or ECHOs of mitral stenosis show?
LA enlargement and maybe afib
How is aortic mitral managed?
Anything to slow heart rate/ reduce fluid overload- beta blockers, diuretics etc
IE prophylaxis
What is heart failure?
Inability of the heart to deliver blood at a rate which meets the requirements of the metabolising tissues despite normal or increased cardiac filling pressures
What are the 4 ways in which heart failure can present?
Valve disease
Systolic dysfunction
Arrhythmia
Diastolic dysfunction
How is heart failure classed?
Class I= no limitation/asymptomatic
Class II= slight limitation
Class III= marked limitation/ symptomatically moderate
Class IV= inability to carry out any physical activity without discomfort/ symptomatically severe
What are the 5 main classes of antihypertensives?
ACE inhibitors
ARBs
Beta blockers
Diuretics
Calcium channel blockers
What are some examples of ACE inhibitors?
Ramipril
Perindopril
Enalapril
What are some examples of ARBs?
Candesartan
Valsartan
Losartan
What are some examples of beta blockers?
Propranolol
Bisoprolol
Metaprolol
What are the 3 types of calcium channel blockers- what are they and give an example of each?
Dihydropyridines (peripheral arterial vasodilators) eg amlodopine
Phenylalkylamines (negatively chonotropic and ionotropic) eg verapamil
Benzothiazepines (heart/peripheral vascular effects) eg diltiazem
What are the 4 classes of duiretics- give an example for each?
Thiazides- act on distal tubules (eg bendroflumethiazide)
Loop duiretics (eg furosemide)
Potassium-sparing duiretics (eg spironolactone)
Aldosterone agonists
What are the possible adverse affects of ACE inhibitors?
Hypotension
Acute renal failure (due to low pressure in efferent arterioles)
Hyperkalaemia
Fetal abnormalities
What are the possible adverse affects of ARBs?
Hypotension
Hyperkalaemia
Renal dysfunction
What are the possible adverse affects of calcium channel blockers and due to what reasons may they occur?
Due to peripheral vasodilation= headaches, oedema, flushing
Due to negative chonotropic effects= bradycardia, AV block
Due to negative ionotropic effects= worsening of cardiac failure
What are the possible adverse affects of beta blockers?
Fatigue
Headaches
Breadycardia
Hypotension (from bradycardia)
Cold peripheries
Erectile dysfunction
(DON’T USE WITH ASTHMA!!!)
What are the possible adverse affects of duiretics?
Hypovolaemia
Hypotension
Hypo- kalaemia, natramia, magnesaemia, calcaemia
Raised uric acid
Erectile dysfunction
Impaired glucose tolerance
What are the classes of Antiarrhythmic drugs (give examples for each)?
Class I= sodium channel blockers (Ia: disopyramdide, Ib: lidocaine, Ic: propafenone)
Class II: beta adrenoreceptor agonists (non selective= propranalol, B1 selective= bisoprolol)
Class III= prolon action potential (amiodarone)
Class IV= calcium channel blockers (verapamil)
What are the hallmarks for anaemia in men and women?
Haemoglobin of lower than 130 in men and 120 in women
What are the 5 types of anaemia?
Haemolytic
Aplastic
Microcytic
Macrocytic
Normocytic
What is haemolytic anaemia?
Increased breakdown of RBCs
What is aplastic anaemia?
Decreased RBCs, WCs and platelets
What is Microcytic anaemia?
Reduced mean RBC volume
What is macrocytic anaemia?
Increased mean RBC volume (seen in haemolytic anaemia because new fresher RBCs are bigger than old ones- that are being killed off)
What is Normocytic anaemia?
Anaemia with normal RBC mean volume (may be a mix of macro and micro?)
What are the features of Microcytic anaemia (when does it occur, what do iron studies show and what may cause it)?
Occurs in iron defficiency and/or thalassaemia
Low ferratin, low iron, raised transferrin and low transferrin saturation
May be caused by infection, inflammation, neoplasia or sickle cell
What are the features of Macrocytic anaemia (when does it occur/ what may cause it)?
Folate and/or B12 deficiency
Seen in haemolytic anaemia
May be caused by pernicious anaemia (lack of intrinsic factor so B12 can’t be absorbed)
What are the main signs of anaemia?
Tachycardia, skin pallor, conjunctiva pallor, intermittent claudication, jaundice, koilonychia (spoon shaped nails seen in iron deficiency)
What are neutrophilia and neutropenia indicative of?
Neutrophilia: infection/inflammation/CML
Neutropenia: antibiotics/chemotherapy/marrow failure/liver disease
What are thrombocytosis and thrombocytopenia indicative of?
Thrombocytosis: infection/inflammation/tissue injury/splenectomy/thrombocythemia
Thrombocytopenia: production failure (from marrow failure or leptospirosis) or increased removal
What are lymphocytosis and lymphocytopenia indicative of?
Lymphpcytosis: EBV/CMV/hepatitis/malignancy or stress
Lymphocytopenia: steroids/HIV/post viral/marrow failure/chemotherapy
What are 6 diseases of clotting?
Sickle cell
Thrombotic thrombocytopenic purpura (TTP)
Immune thrombocytopenic purpura (ITP)
Disseminated intravascular coagulation (DIC)
Haemophilia
Von willebrand’s
How do those in a sickle cell crisis present?
Bone and joint pain
Infection
Dyspnoea
Cough
Hypoxia
(Stroke)
How is sickle cell disease tested for?
Solubility test
Haemoglobin electrophoresis
How do Thombotic thrombocytopenic purpura (TTP) and immune thrombocytopenic purpura (IPT) present?
Fatigue
Fever
Jaundice
(Raised WBCs, low platelets, low Hb)
What is haemophilia?
Haemophilia A= factor 8 deficiency
Haemophilia B= factor 9 deficiency
Presents with soft tissue bleeding into muscles, joints of haemotoma formation
What is Von Willebrand’s disease?
Defect in quality or quantity of Von willibrand’s factor (which protects breakdown of factor 8)
= primarily a disorder of primary haemostasis
What are the types of leukaemia?
Acute lymphoblastic
Chronic lymphoblastic
Acute myeloid
Chronic myeloid
At what age is acute lymphoblastic leukaemia most common?
Children years 0-4
At what age is acute myeloid leukaemia most common?
Elderly
What would a FBC show in acute lymphoblastic leukaemia?
Anaemia
Thrombocytopenia
Neutropenia
What would a FBC show in acute myeloid leukaemia?
Anaemia
Thrombocytopenia
What would a FBC show in chronic lymphoblastic leukaemia?
Anaemia
Thrombocytopenia
Leukocytosis
What would a FBC show in chronic myeloid leukaemia?
Anaemia
Thrombocytopenia
Leukocytosis
Which leukaemia will a bone marrow show auer rods?
Acute myeloid
Which leukaemia is often asymptomatic?
Chronic lymphoblastic
What distinguishes lymphoma as Hodgkin’s or non-hodgkin’s?
Reed sternberg cells which are present in hodgkin’s!!!
What is ann arbor staging of lymphoma?
- Disease in one area only
- Disease in two or more areas on the same side of the diaphragm
- Disease in two or more areas on both sides of the diaphragm
- Spread beyond the lymph nodes
What is multiple myeloma?
Cancer of differentiated B-lymphocytes (plasma cells)
Accumulation of malignant plasma cells in the bone marrow -> progressive bone marrow failure
How does multiple myeloma present?
CRAB
Calcium is high
Renal impairment
Anaemia
Bone lesions
What is polycythaemia?
High concentration of erythrocytes in the blood
(CONCENTRATION)
What are the types of polycythaemia?
Relative= normal no of erythrocytes but reduced plasma
Absolute= increased no of erythrocytes
- primary = polycythaemia Vera (abnormality of bone marrow)
- secondary = overstimulation of bone marrow by external factor
What is polycythaemia Vera?
Myeloproliferative neoplasm
(Abnormality in the bone marrow leading to overproduction of erythrocytes)
How does polycythaemia Vera present?
Headaches, dizziness, fatigue, blurred vision, red skin, hypertension, hepatosplenomegaly, itching
What would a FBC show in polycythaemia vera?
The following all raised:
Haemoglobin, haematocrit, white cell count, platelet count
Decreased serum erythropoietin
What condition is associated with the JAK2 mutation?
Polycythaemia Vera
What mutation is associated with polycythaemia vera?
JAK2
What are the 4 main functions of the liver?
Protein synthesis
Glucose & fat metabolism
Defence (kupffer cells)
Detoxification and excretion
What is the blood supply of the liver?
Blood enters via the portal vein and hepatic artery
Flows into a system of sinusoids
Exits via hepatic/central vein
What are the presentations of acute liver injury?
Malaise
Nausea
Anorexia
Jaundice
(Confusion, bleeding, liver pain, hypoglycaemia)
What are the presentations of chronic liver injury?
Ascites
Oedema
Haematemesis
Malaise
Easy bruising
Hepatomegaly
What do liver function tests measure?
Serum bilirubin
Albumin
Prothrombin time
What are the types of jaundice corresponding to?
Jaundice of unconjugated bilirubin= pre-hepatic
Jaundice of conjugated bilirubin= hepatic or post hepatic
How does pre-hepatic jaundice present?
Normal urine
Normal stool
Normal liver tests
How does cholestatic jaundice present (hepatic or post-hepatic)?
Dark urine
Pale stool
(Itching)
Abnormal liver tests
What are the classifications of gallstones?
Intra hepatic: hepatolithiasis
Extrahepatic: choledocholithaisis
Gallbladder stones: cholecystolithiasis
What do gallbladders consist of?
70% cholesterol
30% pigment +/- calcium
How do bile duct gallstones present?
Biliary pain
No cholesystitis
Obstructive jaundice
Cholangitis
Pancreatitis
How do gall bladder gallstones present?
Biliary pain
Cholecystitis
(Obstructive jaundice)
No cholangitis
No pancreatitis
How are gallbladder stones managed?
Laparoscopic cholecystectomy
Bile acid dissolution therapy
How are bile duct stones managed?
ECRP (endoscopic retrograde cholangiopancreatography) with sphincterectomy and removal/crushing/placement
(Surgery for large stones)
What are the signs/symptoms of chronic liver disease?
Spider naevus (small dilated blood vessels on surface of skin)
Ascites
What is Ascites and how is it managed?
Ascites= fluid retention in abdomen
Caused by portal hypertension from increased hepatic resistance
Managed by fluid and salt reduction, diuretics, large-volume paracentesis (fluid removal)
What are the 6 causes of chronic liver disease?
Alcohol
Non-alcoholic steatohepatitis
Viral hepatitis (B and C)
Immune (incl auto)
Metabolic (incl haemochromatosis and Wilson’s)
Vascular
What are 3 major causes of portal hypertension?
Cirrhosis
Fibrosis
Portal vein thrombosis
What drugs should be avoided in chronic liver disease?
ACE inhibitors
Aminoglycosides
What are the 5 main consequences of chronic liver disease?
Malnutrition
Coagulopathy (bc coag factors are synthesised in liver?)
Infections
Hypo- (natraemia, kalaemia, glycaemia)
What autoantibodies may be present in autoimmune hepatitis?
Antinuclear
Anti-smooth muscle
Liver-kidney microsome
What is primary biliary cholangitis/cirrhosis?
Chronic disease where bile ducts are slowly destroyed (unknown pathogenesis)
What may people with primary biliary cholangitis present with?
Asymptomatically
Itching
Fatigue (-> autonomic neuropathy)
Dry eyes
Joint pain
Variceal bleeding
Liver pain
What is sclerosing cholangitis/cirrhosis?
Inflammation casing scarring within the bile ducts leading to areas of narrowing and sometimes gallstones
